Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[H-].[Na+].[CH2:12]([N:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[C:21](Cl)[C:20]1=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([NH:1][C:2]2[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=2)[C:20]1=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1c(Cl)nc(Cl)cn1Cc1ccccc1
Reactant: Cc1cnc(N)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(Br)c1
Temperature: 72 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
2-Amino-3-bromo-5-methyl-pyridine (1.0 g, 5.35 mmol) was added to a solution of sodium hydride (60%, 321 mg, 8.0 mmol) in dry THF (20 mL) at r.t. under nitrogen. After 30 minutes, 1-benzyl-3,5-dichloro-2(1H)-pyrazinone (see Vekemans, et. al., J. Heterocyclic Chem., 20, (1983), 919-923) (1.36 g, 5.35 mmol) was added, and the reaction stirred at 72° C. for 4 h. The solution was concentrated in vacuo and the residue was dissolved in CH2Cl2. Organics were washed with H2O and brine, dried (MgSO4), and concentrated. Purification by silica gel (2:1:1 hexanes/EtOAc/CH2Cl2) gave 860 mg (40%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 7.29-7.39 (m, 5H), 5.07 (s, 2H), 2.29 (s, 3H). MS (ES) [m+H] calc'd for C17H14BrClN4O, 405, 407; found 405, 407.
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([Cl:14])[S:13][C:8]=2[CH:7]=1)=[O:5])C.[CH2:15]1[NH:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][CH:16]12>>[Cl:14][C:12]1[S:13][C:8]2[CH:7]=[C:6]([C:4]([N:20]3[CH2:19][CH2:18][N:17]4[CH2:21][CH2:22][CH2:23][CH:16]4[CH2:15]3)=[O:5])[NH:10][C:9]=2[CH:11]=1
Reactant: C1CC2CNCCN2C1
Reactant: CCOC(=O)c1cc2sc(Cl)cc2[nH]1
Product: O=C(c1cc2sc(Cl)cc2[nH]1)N1CCN2CCCC2C1
Yield: 30 %

Procedure:
2-Chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (230 mg, 1.0 mmol) was hydrolyzed (Procedure B) and then coupled with octahydro-pyrrolo[1,2-a]pyrazine (Procedure C) to provide the title compound (93 mg, 30% for two steps) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): exact mass calculated for C14H16ClN3OS, 309.07; m/z found, 310.1 [M+H]+. 1H NMR (CDCl3, 400 MHz): 10.9 (br s, 1H), 6.86 (s, 1H), 6.64 (d, J=1.4 Hz, 1H), 4.77 (d, J=12.2 Hz, 1H), 4.65 (d, J=12.7 Hz, 1H), 3.30-2.90 (m, 4H), 2.30-1.40 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[C:12]3[O:14][CH2:15][O:16][C:11]3=[CH:10][C:9]=2[CH2:17][C:18](OC)=[O:19])=O)=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].C(O)(=O)C.O>C(O)C>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[C:8]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:9]=3[CH2:17][C:18](=[O:19])[NH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(F)cc1)OCO2
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc3c(cc2C(c2ccc(F)cc2)=NN1)OCO3

Procedure:
The title compound was prepared from methyl 2-(4-fluorobenzoyl)-4,5-methylenedioxyphenylacetate (350 mg, 1.11 mmol), hydrazine hydrate (180 μL, 3.18 mmol), and acetic acid (50 μL) in ethanol (10 mL), mp: 205°-207° C. 1H NMR (CDCl3) 8.45 (s, 1H), 7.59 (dd, 2H, J=8.5, J=5.5), 7.11 (dd, 2H, J=8.5, J=8.5), 6.83 (s, 1H), 6.61 (s, 1H), 6.04 (s, 2H), 3.45 (s, 2H). Anal. calcd. for C16H11FN2O3.0.125 H2O: C, 63.94; H, 3.77; N, 9.32. Found: C, 63.83; H, 3.58; N, 9.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CC(NCC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one (1.0 g, 5.67 mmol) and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 6.23 mmol) in dichloroethane (50 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (3.0 g, 14.2 mmol, 2.5 eq.) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice more with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography on silica gel eluting with 5% methanol/methylene chloride afforded 4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an oil (2.1 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[N:21]2)[CH:10]=[C:11]([F:19])[C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]([N:20]2[CH:24]=[C:23]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[N:22]=[N:21]2)[CH:10]=[C:11]([F:19])[C:12]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.1 mL, 2.23 mmol) was added dropwise to a solution of [1-(3,5-difluoro-4-morpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-yl]-methanol (0.6 g, 2.02 mmol), obtained in Example 1, and Et3N (0.6 mL, 4.4 mmol) in CH2Cl2 (30 mL) at 0° C. After stirring for 45 min the reaction mixture was washed successively with water, aqueous NaHCO3 and brine and dried over sodium sulfate. Evaporation of volatiles left the title compound as oily liquid (0.7 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cnc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 189g (180 mg, 0.43 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (165 mg, 0.43 mmol), Pd(dppf)Cl2 (35 mg, 0.043 mmol), sodium acetate (71 mg, 0.86 mmol), K3PO4 (194 mg, 0.86 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. After this time the reaction was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 189h as a yellow solid (100 mg, 34%). MS-ESI: [M+H]+ 680.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=2)[C:16]#[N:17])=O)[CH:5]=[CH:4][N:3]=1.Cl[C:22]1[N:27]=[C:26](/[CH:28]=[C:29](/[C:31]2C=CC(OC)=C(C=2)C#N)\O)C=C[N:23]=1.C1C(=O)N(Br)C(=O)C1.NC1C=CC=CN=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:27]3[CH:26]=[CH:28][CH:29]=[CH:31][C:22]3=[N:23][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(/C(O)=C/c2ccnc(Cl)n2)cc1C#N
Reactant: COc1ccc(C(=O)Cc2ccnc(Cl)n2)cc1C#N
Agent: Nc1ccccn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C#N
Temperature: 65 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a tautomeric mixture of 5-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)benzonitrile and 5-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]-2-(methyloxy)benzonitrile (2.87 g, 10.0 mmol) in DCM (250 mL) was added NBS (1.78 g, 10.0 mmol) in one portion. Upon completion by TLC, the reaction was concentrated. The residue was taken up in dioxane (100 mL) and 2-aminopyridine (2.89 g, 30.7 mmol) was added. The reaction was stirred at 65° C. overnight. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4), concentrated and triturated with diethyl ether to provide the title compound (2.36 g, 6.50 mmol, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 3H), 7.18-7.25 (m, 2H), 7.33 (d, J=9.0 Hz, 1H), 7.52-7.58 (m, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.92 (dd, J=8.8, 2.4 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 8.56 (d, J=5.5 Hz, 1H), 9.34-9.39 (m, 1H).
Reaction SMILES: Cl.[Cl:2]CC([NH:6][CH2:7][C:8]1[C:13]([OH:14])=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=1[C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(O)C>[ClH:2].[NH2:6][CH2:7][C:8]1[C:9]([C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:10][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][C:13]=1[OH:14]
Reactant: CC(C)(C)c1cc(O)c(CNC(=O)CCl)c(C(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Temperature: 85 °C

Procedure:
To a solution of 50 mL ethanol and 15 mL conc. hydrochloric acid was added 4.35 g (0.014 mol) of the product of Step A and the reaction mixture was stirred and heated to 85° C. using an external oil bath for 3 h. The reaction mixture was then cooled to room temperature and evaporated in vacuo. Excess water was removed from the product mixture by azeotropic distillation of added portions of toluene on a rotary evaporator. The residue was triturated with ether and dried overnight in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]([C@H:8]1[C:11](=[O:12])[NH:10][C@@H:9]1[CH2:13][C:14]([OH:16])=[O:15])([CH3:7])[CH3:6]>CCOCC.CO.C(O)(=O)C>[OH:4][C:5]([C@H:8]1[C:11](=[O:12])[NH:10][C@@H:9]1[CH2:13][C:14]([O:16][CH3:3])=[O:15])([CH3:7])[CH3:6]
Reactant: CC(C)(O)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C[C@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: 0 °C

Procedure:
A solution of diazomethane in ether (2 ml) was added to a solution of [(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (23 mg) in methanol (3 ml) at 0° C. and the mixture was stirred for an hour at 0° C. Acetic acid (2 drops) was added to the mixture at 0° C. and the mixture was evaporated in vacuo to give methyl [(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetate (25 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]O)=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=2[F:33])=[CH:42][CH:43]=1)=[O:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reactant: OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
First, 2.47 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 1.85 g of 2,3-difluoro-4'-[6-hydroxyhexyl]oxybiphenyl, 1.6 g of triphenylphosphine, and 50 ml of tetrahyrofuran were placed in a 100 ml flask. Then, 1.1 g of diethyl azodicarboxylate was added dropwise to the reaction mixture at 5° C. Thereafter, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to obtain 4 g of 6-[2,3-difluorobiphenyl-4'-yl]oxyhexyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 97.8%). The compound thus obtained had a purity of 99% by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COc1cc(CCN2CCCCC2)c(F)cc1N
Reaction time: 8 h
Yield: 80.8 %

Procedure:
1-{2-[2-fluoro-5-(methyloxy)-4-nitrophenyl]ethyl}piperidine (0.81 g, 2.87 mmol) was placed in a 100 mL high pressure vessel and dissolved in 30 mL of EtOAc. 5 wt % Platinum(sulfided)/carbon (0.559 g, 0.143 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove oxygen. The vessel was then pressurized with H2 (50 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.586 g, 2.32 mmol, 81%). 1H NMR (400 MHz, CD3OD) δ ppm 6.72 (d, J=6.96 Hz, 1H), 6.46 (d, J=11.35 Hz, 1H), 3.81 (s, 3H), 3.21-3.27 (m, 2H), 3.13-3.21 (m, 4H), 2.93-2.99 (m, 2H), 1.82-1.89 (m, 4H), 1.62-1.71 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH3:23])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:25]([CH2:35][CH3:36])[C:26](=O)[C:27]([O:29][CH2:30][CH2:31]CC)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:25]([CH2:35][CH3:36])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH3:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCC)C2)oc1CC
Yield: 90.5 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-ethoxypiperidin-4-yl)carbamate obtained in Example (112f) (0.95 g, 3 mmol), butyl 3-bromo-2-oxopentanoate obtained in Example (106a) (5 g, 19.9 mmol), sodium bicarbonate (0.72 g, 9 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 1.21 g of the title compound as a light yellow oily substance (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:30]([O-:32])=[O:31])=[C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27]C)=[O:25])[C:16]3=[O:29])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].S(=O)(=O)(O)O.CO>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:30]([O-:32])=[O:31])=[C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:16]3=[O:29])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])c1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-{5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-2-nitrophenyl}tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (16.0 g, 0.030 mol) and sulfuric acid (1.60 mL, 0.030 mol) in methanol (240 mL, 5.92 mol) is refluxed overnight, treated with sulfuric acid (0.40 mL), refluxed for 90 minutes, treated with sulfuric acid (0.80 mL), refluxed for 90 minutes, treated with sulfuric acid (0.80 mL), refluxed for 1 hour, treated with sulfuric acid (0.80 mL), refluxed for 90 minutes, stirred at room temperature overnight, partially concentrated in vacuo and diluted with ether. The organic mixture is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid, mp 166°-167° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][C:9]([CH3:11])([CH3:10])[C:4]=2[C:3]=1[C:12]([O:14]CC)=O.O.[CH:18]([NH2:20])=O>>[CH3:10][C:9]1([CH3:11])[C:4]2[C:3]3[C:12](=[O:14])[NH:20][CH:18]=[N:1][C:2]=3[S:6][C:5]=2[CH2:7][CH2:8]1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1C(C)(C)CC2
Solvent: O
Product: CC1(C)CCc2sc3nc[nH]c(=O)c3c21
Temperature: 180 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Ethyl 2-amino-4,4-dimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (2.3 g, 9.9 mmol, 1 equiv.) was dissolved in formamide (12 mL). The mixture was stirred for 1 hour at 180° C. Then water (50 mL) was added and the product extracted with ethyl acetate (50 mL*3). The organic layer was washed with water (100 mL*2) and brine (100 mL), dried by sodium sulfate and filtered. The organic layer was concentrated and the residue purified by column chromatography (hexane:ethyl acetate=6:5) to give the desired product (1.57 g, 75%) as a yellow solid. MS: m/z 221 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(F)ccc43)c2cc1OC
Yield: 81 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 81% yield from 5-fluoro-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq)in i-PrOH. (M.P. 190°-191° C.; LC-MS: 326 (MH+); anal. RP18-HPLC RT: 4.40 min.).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-])=O)=[C:14]([Cl:22])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl-].[NH4+]>CO.O.[Fe]>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH2:19])=[C:14]([Cl:22])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc2cc([N+](=O)[O-])c(Cl)cc2[nH]c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)c1cc2cc(N)c(Cl)cc2[nH]c1=O

Procedure:
A suspension of the compound obtained in Step C (7.0 g, 19.4 mmol), powdered iron (10.8 g, 194 mmol) and ammonium chloride (10.4 g, 194 mmol) is stirred at reflux for 1 hour in a mixture of 270 ml of methanol and 90 ml of water. The suspension is filtered hot over Celite and the solid is rinsed several times with methanol. The filtrate is evaporated to dryness and the residue is suspended in water. The solid is filtered off, rinsing with water and drying to obtain the title product in the form of orange crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccccc1CCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-hydroxypropyl)benzonitrile (Example 323c, 3.83 g) in DMF (40 mL) under nitrogen was treated with 60% Sodium hydride (1.140 g) and stirred at room temperature for 1 h before adding benzyl bromide (2.83 mL). The resulting solution was stirred at 20° C. for 60 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL). The organic was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography eluting with 30% diethyl ether in isohexane). Pure fractions were evaporated to dryness to afford the subtitle compound as an oil (2.3 g).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].C(OC([N:33]1[CH2:37][CH2:36][C:35](=O)[CH2:34]1)=O)(C)(C)C.Cl>>[ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:15][CH2:16][N:17]([CH:35]4[CH2:36][CH2:37][NH:33][CH2:34]4)[CH2:18][CH2:19]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)nc(O)c12
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(C4CCNC4)CC3)nc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 88 reacting via reductive amination 3-ethyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride and 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester followed by de-protection of the adduct with HCl.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.I[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:20][CH3:21])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: CCI
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (300 mg, 0.983 mmol), iodoethane (0.095 mL, 1.180 mmol) and potassium carbonate (408 mg, 2.95 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a brown suspension. This was stirred at 50° C. under a nitrogen atmosphere for 60 minutes. The reaction mixture was diluted with saturated sodium bicarbonate solution (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were washed with 50:50 water:brine (3×5 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown solid. This was purified by Biotage chromatography (25 g silica cartridge, cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the title compound as a beige solid (160 mg, 48.8% yield).