Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[CH3:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>O>[CH3:54][N:55]1[CH2:60][CH2:59][N:58]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)=[O:27])[CH2:57][CH2:56]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(C(=O)c2ccc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Reaction time: 0.08 h
Yield: 18.4 %

Procedure:
To a solution of example 8 (0.100 g, 0.262 mmol) in DMF (1 ml) HOBT (0.042 g, 0.314 mmol), EDC-HCl (0.125 g, 0.655 mmol) and triethylamine (0.1 ml, 0.786 mmol) were added and stirred for 5 min. 4-Methylpiperazine (0.023 g, 0.235 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.020 g, 17%). M.P.: 156-158° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.02 (dd, J=5.1, 3.6 Hz, 2H), 7.83 (dd, J=8.8, 1.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.63 (s, 2H), 3.30 (s, 2H), 2.36 (s, 4H), 2.19 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.[ClH:32]>CO>[ClH:32].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Reactant: NCCc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2NCCc2ccc(F)cc2)cc1=O
Temperature: 120 °C
Yield: 49 %

Procedure:
A suspension of 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (0.60 g, 2.07 mmol), and 2-(4-fluorophenyl)ethylamine (2.9 g, 20.8 mmol) was heated at 120° C. for 8 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish a colorless oil. The methanol (10 ml) solution of resulting oil was treated with 4N hydrochloric acid (5 ml). The residue obtained by evaporation was washed by ethyl acetate to furnish 6-(3-(2-(4-fluorophenyl)ethylamino)pyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one hydrochloride (0.45 g, 1.01 mmol, 49%) as white crystals.
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)(=O)[CH3:20]>ClCCl>[CH2:19]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:32])=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)[CH3:20]
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)C[N+](=O)[O-])ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: CCN1CCc2cc(S(=O)(=O)C[N+](=O)[O-])ccc21

Procedure:
Tetrabutylammonium borohydride (3.85 g, 15 mM) was added to a solution of 1-acetyl-5-(nitromethylsulphonyl)indoline (1.45 g, 5 mM) in dichloromethane (30 ml), and the mixture was stirred at reflux for 18 hours. The solvent was removed by evaporation, 2M hydrochloric acid (30 ml) was added, and the mixture was heated at reflux for 20 minutes. The solution was then poured into sufficient of an ice-cold saturated solution of sodium hydrogen carbonate to adjust the mixture to pH 6. The mixture was then extracted with dichloromethane, the combined extracts were dried (MgSO4), and the solvent was removed by evaporation. The resultant yellow oil was purified by vacuum flash chromatography on silica, eluting with dichloromethane, to give 1-ethyl-5-(nitromethylsulphony)indoline as a solid, m.p. 122° C.; NMR (d6 -DMSO): 1.1(3H,t), 3.0(2H,t), 3.3(2H,m), 3.6(2H,t), 6.3(2H,s), 6.6(1H,d), 7.4(1H,d), 7.5(1H,dd); microanalysis, found: C,49.3; H,5.1; N,10.4%; C11H14N2O4S requires: C,48.9; H,5.2; N,10.4%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10](Br)=[N:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using compound 1a (0.20 g, 0.84 mmol) and phenylboronic acid (0.20 g, 1.68 mmol) according to Method B. Yellow solid. Yield: 0.10 g, 57%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.19 (s, 2H), 6.94 (t, J=1.3 Hz, 1H), 7.13 (s, 1H), 7.48-7.50 (m, 4H), 7.60 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.97-7.99 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.0, 120.6, 126.9, 128.8, 130.0, 130.4, 135.7, 137.3, 138.6, 148.6, 157.7; MS (ESI): m/z=236.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]1[OH:23].[C:24]([O:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36]#[CH:37])[CH2:31][CH2:30]1)(=[O:26])[CH3:25]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([O:27][CH2:28][CH:29]1[CH2:30][CH2:31][CH:32]([CH2:35][C:36]#[C:37][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[C@H:12]3[C@H:13]([OH:23])[C@H:14]([OH:22])[C@@H:15]([C:17](=[O:18])[NH:19][CH2:20][CH3:21])[O:16]3)=[C:2]([NH2:1])[N:10]=2)[CH2:33][CH2:34]1)(=[O:26])[CH3:25]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)[C@H](O)[C@@H]1O
Reactant: C#CCC1CCC(COC(C)=O)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(COC(C)=O)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a degassed solution of 125 mg (0.29 mmol) of [(2S,3S,4R,5R)-5-(6amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]-N-ethylcarboxamide (6.9), 150 mg (0.77 mmol) (5.6), and 1.0 mg CuI in 1.3 mL of TEA and 4 mL DMF was added 25 mg of Pd(PPh3)4. The solution was stirred for 72 h at 60° C. after which time the solution was filtered through celite and chromatographed on silica gel with MeOH-CHCl3 (5:95) to give JMR193 (10%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH3:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1ccccc1B(O)O
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Yield: 70.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-methylphenylboronic acid (106 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 146 mg (70%) of the title compound as an amorphous solid. mp 82°-87°. FDMS: m/e=319. α[D]589 =+63.96 (c=0.35, chloroform).
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[NH2:14][C:15](=O)[CH2:16][C@H:17]([C:47](=[O:65])[NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])[CH2:18][CH2:19][C@H:20]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C@H:24]1[CH2:30][CH2:29][S:28][C@H:27]2[CH2:31][CH2:32][CH2:33][C@@H:34]([C:35]([O:37][CH3:38])=[O:36])[N:26]2[C:25]1=[O:39])=[O:22]>C(Cl)Cl>[CH2:40]([C@@H:20]([CH2:19][CH2:18][C@H:17]([CH2:16][C:15]#[N:14])[C:47]([NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])=[O:65])[C:21]([NH:23][C@H:24]1[CH2:30][CH2:29][S:28][C@H:27]2[CH2:31][CH2:32][CH2:33][C@@H:34]([C:35]([O:37][CH3:38])=[O:36])[N:26]2[C:25]1=[O:39])=[O:22])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(N)=O)C(=O)N21
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](CC#N)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)Cc3ccccc3)C(=O)N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
TFAA (15 mg, 0.069 mmol) was slowly added to a 0° C. solution of Example 29 (27 mg, 0.034 mmol) and TEA (12.2 mg, 0.121 mmol) in DCM (0.25 mL). The reaction mixture was then stirred at rt for 1.5 hr. The reaction mixture was concentrated and the residue was partitioned between EtOAc and 10% aqueous Na2CO3. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by RP prep-HPLC (Method A) to give dimethyl (4S,7S,10aS,4′S,7′S,10a′S)-4,4′-(((2R,5R)-2-benzyl-5-(cyanomethyl)-1,6-dioxo-1,6-hexanediyl)diimino)bis(5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate) (13 mg, 0.018 mmol, 51% yield). Anal. Calcd. for C37H49N5O8S2 m/z 755.7. found: 756.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, d, J=6.6 Hz), 7.30-7.21 (3H, m), 7.20-7.11 (3H, m), 5.44-5.35 (2H, m), 5.18-5.00 (4H, m), 3.72 (3H, s), 3.69 (3H, s), 3.20 (1H, ddd, J=14.0, 10.7, 2.7 Hz), 3.15-3.01 (3H, m), 2.96 (1H, ddd, J=14.4, 7.0, 2.7 Hz), 2.91-2.82 (2H, m), 2.71 (1H, dd, J=13.2, 6.6 Hz), 2.65-2.55 (2H, m), 2.53-2.35 (4H, m), 2.25 (1H, ddd, J=10.7, 6.9, 3.3 Hz), 2.09-1.96 (4H, m), 1.82 (1H, td, J=7.1, 3.8 Hz), 1.78-1.51 (10H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2ccc(-c3ccccc3)cc2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylate (0.25 g, 0.74 mmol) in a mixture of tetrahydrofuran (4 mL) and water (4 mL) was added lithium hydroxide (0.14 g, 3.68 mmol). The reaction mixture was heated at 50° C. for 4 hours, then cooled to ambient temperature and acidified to pH 6 with acetic acid. The solid obtained was collected by filtration, washed with water and dried in air. The title compound was obtained as a yellowish solid (0.20 g, 87%): MS (ES+) m/z 313.5 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=O)[CH2:28]1)[CH3:26].CN1CCOCC1.[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[S:51]([NH:54][C:55]1[C:64]([C:65]([O:67][CH3:68])=[O:66])=[C:63]2[C:58]([CH:59]3[CH2:69][CH:60]3[CH2:61][O:62]2)=[CH:57][CH:56]=1)(=[O:53])=[O:52]>CN(C=O)C.O>[CH2:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([NH:42][CH2:43][C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[S:51]([NH:54][C:55]2[C:64]([C:65]([O:67][CH3:68])=[O:66])=[C:63]3[C:58]([CH:59]4[CH2:69][CH:60]4[CH2:61][O:62]3)=[CH:57][CH:56]=2)(=[O:52])=[O:53])=[O:34])[CH2:28]1)[CH3:26]
Reactant: CCN1CC[C@H](C(=O)O)C1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN)ccc2c1OCC1CC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC[C@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
HATU (0.234 g) was added to a mixture of (S)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 189, 0.089 g) and NMM (0.068 mL) in DMF (4 mL) and the mixture was stirred for 15 minutes. Methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 102, 0.250 g) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15% to give methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.190 g) as a solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Cl:11])(Cl)=[O:9].[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CC1CCCCC1.C1(C)C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([Cl:11])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: CCCCCNC
Solvent: CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCN(C)C(=O)Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Triethylamine (14 cc.) is added over the course of 8 minutes to a 2.5N solution (42 cc.) of phosgene in methylcyclohexane, cooled to -10° C., and a solution of N-methylpentylamine (13.7 cc.) in toluene (50 cc.) is then added whilst maintaining the temperature at -10° C. The mixture is stirred for 1 hour at +5° C. The insoluble material is then filtered off and washed with toluene (80 cc.). The organic solutions are dried over calcium chloride (10 g.). After filtration, the solvents are evaporated under reduced pressure (40 mm.Hg). The residue is distilled under reduced pressure to give N-methyl-N-pentylcarbamoyl chloride (5.6 g.), b.p. 120°-125° C./40 mm.Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23)=[O:35]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CCl)ccc31)Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 10.2 g (0.030 mol) of 5-amino-N,N-diethyl-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 8.3 ml (0.060 mol) of Et3N in 90 ml of CHCl3 was treated dropwise with a solution of 3.6 ml (0.045 mol) of chloroacetyl chloride in 20 ml of CHCl3 over ten minutes. The reaction mixture was stirred at room temperature for three hours, treated with an additional 1.2 ml (0.015 mol) of chloroacetyl chloride in 50 ml of CHCl3, and concentrated to dryness in vacuo. The residue was triturated three times with cold MeOH to give 8.3 g of product, mp 204°-205° C. dec.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:15][CH3:16].[Br:17]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH2:8][Br:17])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:15][CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)c(Br)c(OC)c(OC)c1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Yield: 99.5 %

Procedure:
An ethyl acetate (300 ml) solution of 1-bromo-2,3,4,5-tetramethoxy-6-methylbenzene (49.5 g, 0.170 mols), N-bromosuccinimide (31.8 g, 0.179 mols) and AIBN (558 mg, 3.40 mmols) was heated under reflux for 1 hour. The reaction mixture was concentrated in vacuo, and then diluted with hexane. The resulting crystals were separated by filtration, and the filtrate was concentrated to obtain the entitled compound (62.6 g) as an oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)(=[O:10])=[O:9].C(ON=O)(C)(C)C>C(O)(=O)C>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]2[C:21]([N:20]=1)=[C:12]1[C:13]([C:4]3[C:3]([S:8](=[O:10])(=[O:9])[NH:11]1)=[CH:2][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:15]=2
Reactant: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3N)c2n1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: Cc1ccc2ccc3c(c2n1)NS(=O)(=O)c1ccccc1-3
Temperature: 10 °C
Yield: 4.5 %

Procedure:
2-Amino-N-(2-methyl-quinolin-8-yl)-benzenesulfonamide (Example Compound 15) (164 mg, 0.52 mmol) was suspended in acetic acid (3 ml) and cooled to 10° C. Tert-butylnitrite (93 μl, 0.79 mmol) was added and the reaction was slowly warmed to room temperature over 1 h. The reaction was then quenched with water (4 ml) and the resulting solution was concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (7 mg, 5%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:36][CH3:37])([OH:35])[CH2:33][CH3:34])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][C:16]=2[CH3:41])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[Cl-].[NH4+]>CO.O1CCCC1>[CH2:22]([C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([CH2:6][C:5]([OH:42])=[O:4])[CH:8]=2)=[C:16]([CH3:41])[CH:17]=1)([C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:33][CH3:34])([OH:35])[CH2:36][CH3:37])=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(OC)c(CC(=O)OC)c3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(OC)c(CC(=O)O)c3)c(C)c2)cc1C)CC
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.303 mL, 0.303 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-4-methoxy-2′-methyl-biphenyl-3-yl)-acetic acid methyl ester (Example 181-(1); 54.7 mg, 0.101 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for two hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (41.9 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH3:12].[N+](C1C=CC=C(C(F)(F)F)C=1C)([O-])=O.[Br:27]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:12][Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1C(F)(F)F
Agent: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Product: FC(F)(F)c1cccc(Br)c1CBr

Procedure:
The methyl group of 2-bromo-6-trifluoromethyltoluene was brominated by reacting 47.8 g. of the toluene with 39.2 g. of N-bromosuccinimide under ultraviolet radiation. 77.5 g. of an orange oil comprising 2-bromo-6-trifluoromethylbenzyl bromide were obtained.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[F:24][C:25]([F:34])([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:26][NH2:27]>>[F:34][C:25]([F:24])([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:26][NH:27][C:13](=[O:15])[CH2:12][N:7]1[C:8]([CH3:11])=[CH:9][N:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:6]1=[O:16]
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Reactant: NCC(F)(F)c1ccncc1
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCC(F)(F)c1ccncc1

Procedure:
7-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-ylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 2,2-difluoro-2-(4-pyridyl)ethyl amine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1) 465.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C([O-])([O-])=O.[K+].[K+].CN(C)CC(O)=O>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:12][C:4]1[CH:3]=[C:2]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Br)cc(-n2ccnc2)c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
A mixture of 1,3-dibromo-5-tert-butylbenzene (2.92 g, 10.0 mmol, 1.0 eq), 1H-imidazole (0.69 g, 10.0 mmol, 1.0 eq), CuI (0.19 g, 1.0 mmol, 0.10 eq), K2CO3 (2.76 g, 20.0 mmol, 2.0 eq) and 2-(dimethylamino)acetic acid (0.21 g, 2.0 mmol, 0.20 eq) in DMSO (10 mL) was stirred at a temperature of 110° C. for four days under a nitrogen atmosphere, then cooled down to ambient temperature. The mixture was diluted with plenty of ethyl acetate and filtered. The filtrate was washed with water three times, dried over sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography on silica gel using hexane and ethyl acetate as an eluent to obtain the desired product, 1-(3-bromo-5-tert-butylphenyl)-1H-imidazole 7, as a brown sticky liquid (1.56 g in 56% yield).