Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25]>C1COCC1>[CH3:13][O:14][C:15]1[C:16]([CH2:21][C:22]([O:23][CH2:24][CH3:25])=[O:26])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccnc1C
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ncccc1OC
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A stirred solution of diisopropylamine (0.385 mL, 2.70 mmol) in THF (2 mL) at 0° C. was treated slowly with 1.6 M n-butyllithium in hexanes (1.69 mL, 2.70 mmol). The mixture was stirred for 15 min, then was added over 5 min to a stirred solution of 3-methoxy-2-picoline (0.133 g, 1.08 mmol) and diethyl carbonate (0.262 mL, 2.16 mmol) in THF (5 mL) at −78° C. After stirring for 45 min more, the cooling bath was removed and stirring was continued overnight at room temperature. The mixture was treated with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was separated, washed sequentially with saturated aqueous NaHCO3 and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with 50% EtOAc-hexanes, to provide ethyl 2-(3-methoxypyridin-2-yl)acetate as an oil (0.17 g, 81% yield). Mass spectrum m/z 196 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:31]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 3-(4-methylpiperazin-1-yl)aniline (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=8.0 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.66-7.59 (m, 2H), 7.54-7.49 (m, 1H), 7.27-7.23 (m, 1H), 7.21 (t, J=8.2 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 6.72-6.67 (m, 2H), 6.57 (dd, J=8.2, 1.6 Hz, 1H), 6.43 (d, J=7.6 hZ, 1H), 5.33 (t, J=6.1 Hz, 1H), 4.96 (d, J=6.2 Hz, 2H), 3.29-3.24 (m, 4H), 3.16 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([NH:15][CH2:13][CH3:14])[N:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: CC(C)Nc1nc(Cl)nc(Cl)n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
To the solution of 2,4-dichloro-6-isopropylamino-s-triazine in toluene remaining in the reactor are added, under strong agitation, about 915 g of an aqueous solution containing 50% by weight of ethylamine (10.15 moles) and about 1353 g of an aqueous solution containing 30% by weight of sodium hydroxide (10.15 moles). The said solutions are added in the same manner as in the first reaction step. During the second addition the temperature rises from 25° to 50° C. and the final pH is equal to 11.-12. The dense suspension thus obtained is divided into two parts as quickly as possible. One part (A) is submitted to distillation to remove the toluene in the form of an azeotropic toluene-water mixture, by operating at 85°-100° C. To the distillation residue are added 3,700 ml of water and the suspension thus obtained is filtered at 60° C. The filtered solid is washed until the sodium chloride has been removed completely. After drying for ten hours in an oven at 100° C., 2-chloro-4-ethylamino-6-isopropylamino-s-triazine is obtained with a yield of the orde of 96%.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]=O>>[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[C:41]2[CH:47]=[C:15]1[C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:28])[C:16]1=[O:17]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccc(F)cc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 65.4 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (120 mg, 0.207 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (48 mg, 0.248 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 7% MeOH in CH2Cl2) yielded 85 mg of 2-[4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. MS 628.8 (M+1), 626.4 (M−1).
Reaction SMILES: [CH3:1][CH:2]([CH:5]=[CH2:6])[CH2:3][OH:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH2:3][O:4][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH:5]=[CH2:6]
Reactant: C1=COCCC1
Reactant: C=CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=CC(C)COC1CCCCO1
Yield: 75.3 %

Procedure:
To a suspension of magnesium turnings (50.4 g, 2.1 m) in ether (1500 ml) under a nitrogen atmosphere is added a solution of crotyl bromide (135.0 g, 1.0 m) in ether (125 ml), at room temperature over a period of four hours. The reaction mixture is then cooled to 0° C. and formaldehyde [formed by pyrolysis of paraformaldehyde (45.0 g, 0.5 ml)] is bubbled through the mixture. The resulting mixture is allowed to come to room temperature and stirred overnight. The reaction mixture is then decanted into a solution of ammonium chloride (212 g, 4.0 m) in ice water (2 l). The mixture is extracted with ether (2×3000 ml) and the combined ether extracts are dried (Na2SO4) and filtered. The solvent is removed in vacuo to give 57.2 g of 2-methyl-3-buten-1-ol (66%); nmr (CDCl3,δ): 0.99 (d, J=7 Hz, 3H, ##STR18## 2.10-2.70 (m, 1H, ##STR19## 3.30-3.60 (bd, J=6 Hz, 2H, ##STR20## 4.83-6.13 (m, 3H, vinyl protons); ir(neat): 3257, 1640 cm-1. (b) A solution of 2-methyl-3-buten-1-ol (54.16 g, 0.63 m), dihydropyran (52.92 g, 0.63 m), and p-toluenesulfonic acid (0.5 g) in ether (800 ml) is stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture is then diluted with ether (1 l) and washed with 5% sodium bicarbonate solution (1 l). The ether extract is dried (Na2SO4), filtered and solvent removed in vacuo to give 95.8 g of crude product. The crude product is purified by column chromatography on silica gel (500 g, hexane) to give (75%) 3-methyl-4-(tetrahydropyran-2-yloxy)-1-butene (80.62 g). ##STR21##
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C=CC(Cl)=C.Cl>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.ClC1C=CC=CC=1.O>[Cl:9][C:10]1[CH2:15][C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]=2[CH2:12][CH:11]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: O=C1C=C(Cl)C(=O)O1
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 92 °C
Reaction time: 16 h
Yield: 498.4 %

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing additional funnel, a thermocouple well with a thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 6.62 g (0.05 mol) of monochloromaleic anhydride contaminated with approximately 0.005 mol of dichloromaleic anhydride, 6.1 g of monochlorobenzene and 100 mg of phenothiazine. The contents of the flask were heated to 92° C. and 4.42 g (0.05 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 16 hours at 92° C., the solvent was removed in-vacuo and triturated with 10 mL of diethyl ether to yield 4.6 g (50% of theoretical) of 4-chloro-3,6-dihydrophthalic anhydride. High resolution mass spectrometry (MS) of the solid resulted in the following analysis: Calculated mass=183.99271; observed mass=183.9924. 13C and 1H nuclear magnetic resonance (NMR) spectra were consistent with the assigned structure.
Reaction SMILES: CNC(=O)C1C=CC=C([C:10]2[CH:15]=[CH:14][C:13]([O:16][C@@H:17]3[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3)=[C:12]([CH3:28])[CH:11]=2)C=1.C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H](OC2C=CC(Br)=CC=2C)[C@H]1CC([O-])=O)(=O)C.[CH3:62][O:63][C:64]([C:66]1[CH:67]=[C:68](B(O)O)[CH:69]=[CH:70][CH:71]=1)=[O:65]>>[CH3:28][C:12]1[CH:11]=[C:10]([C:68]2[CH:67]=[C:66]([CH:71]=[CH:70][CH:69]=2)[C:64]([O:63][CH3:62])=[O:65])[CH:15]=[CH:14][C:13]=1[O:16][C@@H:17]1[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Agent: CC(=O)OC[C@H]1O[C@H](Oc2ccc(Br)cc2C)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Yield: 54 %

Procedure:
4c was prepared using the same procedure as for 5b with [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-(4-bromo-2-methyl-phenoxy)tetrahydropyran-3-yl]acetate and 3-methoxycarbonylphenyl boronic acid as the reactants. Yield: 54%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 8.20 (t, J=1.51 Hz, 1H), 7.94 (td, J=1.41, 7.90 Hz, 1H), 7.77-7.87 (m, 1H), 7.52 (t, J=7.55 Hz, 1H), 7.39-7.48 (m, 2H), 7.27-7.38 (m, 1H), 5.56 (d, J=1.65 Hz, 1H), 4.08 (dd, J=1.92, 3.30 Hz, 1H), 3.94-4.01 (m, 1H), 3.90-3.94 (m, 3H), 3.68-3.83 (m, 3H), 3.55-3.65 (m, 1H), 2.31 (s, 3H). MS (ESI): found [M+Na]+, 427.1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.ClCCl>[Cl:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[CH2:8][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CN2CCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.50 g (74.452 mmol) potassium carbonate was added to a solution of 7.400 g (29.543 mmol) of 1-bromomethyl-2-chloro-4-nitro-benzene and 5.00 mL (59.300 mmol) pyrrolidine in 150 mL acetonitrile and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with 200 mL dichloromethane, filtered and the filtrate evaporated down i. vac. The residue was taken up in EtOAc, the org. phase was washed with water, dried over magnesium sulphate and evaporated down i. vac. The crude product was used in the next reaction step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:32])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[C:23]3(Br)Br)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[C:3](=[O:32])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CC(=O)N2
Reaction time: 48 h
Yield: 81.9 %

Procedure:
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-3,3-dibromo-1H-indol-2-one (0.2 g, 0.34 mmol) was suspended in 5 mL of acetic acid, and zinc metal (0.22 g, 3.4 mmol) was added. The reaction was stirred for 48 hours. The reaction was diluted with water, and washed 2 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (0.12 g, 82%): 1H NMR (300 MHz, DMSO-d6) δ 10.37 (br s, 1H), 7.65 (app q, J=6.9 Hz, 1H), 7.34 (dt, J=8.2, 2.5 Hz, 1H), 7.18 (dt, J=7.1, 1.9, 1H), 6.98 (br s, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 5.28 (s, 2H), 5.23 (s, 2H), 3.44 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:3]=1.Cl.[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:2]3[N:7]4[N:8]=[C:9]([CH:11]5[CH2:16][CH2:15][N:14]([CH:17]([CH3:18])[CH3:19])[CH2:13][CH2:12]5)[N:10]=[C:6]4[CH:5]=[C:4]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[N:3]=3)[CH2:44]2)[N:31]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine, 81.2 mg (0.24 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 56 mg (42% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](OC)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1>CN(C)C=O>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH:2][CH3:1])=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: CN
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Solvent: CN(C)C=O
Product: CNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
1.1 cc (0.012 mole) of a 35% aqueous solution of CH3NH2 is gradually dripped into a stirred solution of 2.82 g (0.01 mole) of 4-bromo-1-methoxy-2-nitronaphthalene in 20 cc of dimethylformamide heated to 60° C. The reaction mixture is stirred at 60° C. for 10 minutes then cooled to 0° C. and filtered, yielding 1.81 g of 4-bromo-N-methyl-2-nitro-1-naphthylamine. Further, an addtional 0.79 g of this compound is obtained from the mother liquors by dilution with water. Overall yield 92%. M.p. 187°-188° C. (from Ethanol). A mixture of 35.3 g (0.1255 mole) of 4-bromo-N-methyl-2-nitro-1-naphthylamine, 1.8 g of 10% Pd-C catalyst, and 600 cc of methanol containing 17.6 cc (0.1255 mole) of triethylamine is shaken in a Paar hydrogenator under about 5 atm. of hydrogen pressure for 11/2 hours, until the theoretical amount of hydrogen is adsorbed, then the catalyst is filtered off under argon atmosphere and the mother liquor is concentrated to dryness. The residue is taken up with 250 cc of benzene and filtered again under argon over celite and bleaching earth FF. By evaporating the solvent, 19.73 g (0.115 mole) of N1 -methyl-1,2-naphthyldiamine is obtained as a dark oil. To a mixture of this compound and 16.1 cc (0.115 mole) of triethylamine in 500 cc of methylene chloride cooled to 0°-5° C. and kept under argon atmosphere, a solution of 14.55 g (0.115 mole) of 3-chloropropanoyl chloride in 140 cc of anhydrous methylene chloride is added dropwise. When the addition is terminated, the reaction mixture is allowed to stand at room temperature for a few hours and then it is heated at reflux temperature for 1/2 hour. The pH is brought to 7 by the addition of 2 cc of triethylamine and the reaction mixture is warmed to 35° C. for two hours, washed with water and dried. The raw product (25.5 g) which is obtained by evaporating the solvent is taken up with 160 cc of 5% HCl and stirred at 60° C. for 3 hours. The solids which are insoluble at this temperature are separated by filtration and discarded while the solution is decolorized with activated carbon. The clear solution is cooled to 0° C. and made alkaline with NH4OH. The product which precipitates is separated by filtration and recrystallized from 95% Ethanol. Yield 57.6%. M.p. 251° C. (dec.).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=2Cl)(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:27].Cl>O1CCOCC1>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=2[OH:27])(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1Cl
Reactant: O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1O
Yield: 105.9 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[3-(4-morpholinyl)propyl]-2,6-dichloro-3-nitrobenzenesulfonamide (10 g, 2.51 mmol), 60% NaH (301 mg, 7.53 mmol) and water (54 μL, 3.0 mmol) were reacted. The mixture was acidified with 4.ON HCl in 1,4-dioxane and concentrated to give the crude product (1.01 g), which was carried onto the next steps without purification. LC-MS 380.0 (M+).
Reaction SMILES: ClC1C=C(NC2N=C(C3C(C4C=C(NC(=O)C5C(F)=CC=CC=5F)C=CC=4)=NN4C=CC=CC=34)C=CN=2)C=CC=1OCCN(C)C.[CH3:47][O:48][CH2:49][CH2:50][OH:51].[H-].[Na+].[F:54][C:55]1[CH:56]=[C:57]([N+:62]([O-:64])=[O:63])[CH:58]=[CH:59][C:60]=1F>>[F:54][C:55]1[CH:56]=[C:57]([N+:62]([O-:64])=[O:63])[CH:58]=[CH:59][C:60]=1[O:51][CH2:50][CH2:49][O:48][CH3:47]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COCCO
Agent: CN(C)CCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
In a procedure analogous to Example 125, 0.64 g of the title compound was prepared from 0.39 mL (4.94 mmol) of 2-methoxyethanol, 0.24 g (6.11 mmol) of a 60% mineral oil dispersion of sodium hydride, and 0.75 g (4.7 mmol) of 3,4-difluoronitrobenzene as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 3.44 (s, 3H), 3.80 (d, 2H, J=4.6 Hz), 4.28 (t, 2H, J=4.6 Hz), 7.05 (dd, 1H, J=8.4 and 8.4 Hz), 7.98 (dd, 1H, J=10.6 and 2.7 Hz), and 8.03 (d, 1H, J=9.0 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(OCCO)C>>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1ncnc2c1sc1ncccc12
Solvent: CCOCCO
Product: Brc1cccc(Nc2ncnc3c2sc2ncccc23)c1
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 4-chloropyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine (72 mg, 0.32 mmol) (see previous experimental), 3-bromoaniline (0.04 mL, 0.37 mmol) and 2-ethoxyethanol (5 mL) is heated under N2 with stirring at 135 C. for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at ~80 C. to give 4-(3-bromoanilino)pyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine (45 mg, 39.4%). 1H NMR (DMSO) δ9.96 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz), 8.85 (1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.20 (1H, t, J=2.0 Hz), 7.84 (1H, ddd, J=8.0, 2.0, 1.3 Hz), 7.69 (1H, dd, J=8.0, 4.7 Hz), 7.39-7.31 (2H, m).
Reaction SMILES: [C:1]1([N+:7]#[N:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N=NN>>[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:8]=[N:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#[N+]c1ccccc1
Reactant: Nc1ccccc1
Agent: N=NN
Product: Nc1ccccc1N=Nc1ccccc1

Procedure:
In the examples which follow, the yield of benzenediazonium salt was determined by reacting the benzenediazonium solution with aniline and then rearranging the intermediate triazene to give aminoazobenzene. Thus, the solution containing the diazonium salt was charged into a mixture containing aniline, in large excess (5 to 7 times the theoretical amount), aniline hydrochloride, in half the stoichiometric amount relative to the aniline, and water. The mixture was maintained at 50° C. and aminoazobenzene (ortho and para isomers) was obtained very rapidly in quantitative yield. The excess aniline hydrochloride was then neutralized, the aniline and the aminoazobenzene were extracted with ethyl acetate, and the ethyl acetate and the aniline were distilled. This yields crude aminoazobenzene (ortho+para), the composition of which was determined by vapor phase chromatography.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[CH2:17]3)[CH2:9]1
Reactant: CCN1C(=O)Cc2cc(N3C[C@@H](CN)OC3=O)cc(F)c21
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC)OC3=O)cc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.117 ml, 1.53 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (0.414 g, 1.02 mmol) and diisopropylethylamine (0.709 ml, 4.06 mmol) in dichloromethane (5 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as a yellow solid. HPLC r.t. 4.04 min; 1H NMR (300 MHz, CDCl3) 7.30 (s, 1H), 7.23 (dd, J=2, 13.2 Hz, 1H), 5.13 (t, 1H), 4.74-4.81 (m, 1H), 4.03 (t, J=9.2 Hz, 1H), 3.90 (q, J=6.8 Hz, 2H), 3.80 (dd, J=6.8, 9.2 Hz, 1H), 3.69 (s, 3H), 3.53-3.67 (m, 2H), 1.28 (t, J=6.8 Hz, 3H); MS for C16H18FN3O5 m/z 352.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][NH2:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>>[CH:26]1([C:23]2[NH:24][N:25]=[C:21]([NH:20][C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:12][CH2:11][C:3]4[C:2]([CH3:1])=[CH:10][CH:9]=[C:8]5[C:4]=4[CH:5]=[CH:6][NH:7]5)[N:19]=3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc2[nH]ccc2c1CN
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2[nH]ccc2c1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A mixture of 304 (53 mg, 0.331 mmol) 53 (94 mg, 0.397 mmol), and DIPEA (128 mg, 0.993 mmol) in WA (2 mL) under nitrogen atmosphere was heated in a sealed tube at 120° C. for 18 h. The crude was purified by preparative HPLC to afford 38 mg (32%) of I-122.