Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:34])=[C:9]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:6][C:7]2[C:8]([CH3:34])=[C:9]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][N:36]([CH3:37])[CH3:35])=[CH:17][CH:18]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (0.11 g, 0.24 mmol) and N,N-dimethylamine (0.044 g, 1.2 mmol) in methanol (3 mL) was added acetic acid (0.014 g, 0.24 mmol) and the solution stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.030 g, 0.48 mmol) was added and the solution stirred overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography over silica gel to afford desired 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-((dimethylamino)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxamide
Reaction SMILES: [NH2:1][CH:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[OH:4][CH2:3][CH:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
To a mixture of 5.0 g (32.14 mmol) of D,L-serine, methyl ester and 15.7 ml (0.012 mol) of triethylamine in 100 ml of CH2Cl2, cooled to 0° C., was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2Cl2 and then washed with 60 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a solid. Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94° C. Anal. for C11H15NO6S: Calc'd: C, 45.7; H, 5.2; N, 4.8; S, 11.1; Found: C, 45.6; H, 5.2; N, 4.8; S, 11.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:3]2[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(F)c1
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Yield: 55.9 %

Procedure:
Using a procedure analogous to Example A1, 2-fluoro-4-aminophenol (2.6 g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined to provide 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.2 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90 (m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H); MS (ESI) m/z: 239.1 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]1[C:24](=[O:34])[NH:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:24]([C@@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[C:12](=[O:13])[C@@H:8]([NH2:7])[CH:9]([CH3:11])[CH3:10])=[O:34]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(S)-1-[(S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (47 mg, 93.3 μmol, Eq: 1.00) in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to provide (S)-2-((S)-2-amino-3-methyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:42])=[C:13]([N:15]2[C:22](=[O:23])[C:21]3[CH:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[N:18]([CH:32]([CH3:34])[CH3:33])[C:17]=3[CH:16]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:14]=1.CN(C=O)C>CC#N>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:42])=[C:13]([N:15]2[C:22](=[O:23])[C:21]3[C:20]([C:6]#[N:5])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[N:18]([CH:32]([CH3:34])[CH3:33])[C:17]=3[CH:16]2[C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH:14]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c(C#N)c2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Chlorosulfonyl isocyanate [1189-71-5] (0.453 mmol) was added to a mixture of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.302 mmol) in CH3CN (2 mL) at 0° C. After stirring at rt for 2.5 h, additional chlorosulfonyl isocyanate (0.226 mmol) was added. After another 4 h, the reaction mixture was cooled to 0° C., treated with DMF (0.4 mL), stirred for 15 min and then warmed to 50° C. After 30 min, the reaction mixture was cooled to rt, poured onto ice-H2O and extracted with EtOAc. The organic layer was successively washed with a 1N aqueous solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as an off-white solid. tR: 5.59 min (HPLC 1); ESI-MS: tR=1.39 min, [M+H]+ 530/532/534 (LC-MS 1); TLC: Rf=0.12 (1:3 EtOAc/heptanes); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 7.79/7.83 (s, 1H), 7.58 (m, 1H), 7.35-7.46 (m, 3H), 7.31 (m, 2H), 7.25 (m, 1H), 7.21 (m, 1H), 7.09-7.17 (m, 2H), 6.61 (s, 1H), 3.97/4.01 (m, 1H), 3.77/3.83 (s, 3H), 1.93 (s, 3H), 1.26/1.35 (m, 3H), 0.42/0.58 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH2:3][CH2:4][OH:5]
Reactant: S
Reactant: CC(CN(C)CCO)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(CN(C)CCO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 10-{(2RS)-1-[N-methyl-N-(2-hydroxyethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (3.1 g) and triethylamine (1.3 cc) in anhydrous pyridine (62 cc) is treated with hydrogen sulphide. The greenish solution obtained is then stirred for 16 hours at a temperature in the region of 20° C., purged with nitrogen, poured into distilled water (500 cc) and extracted with ethyl acetate (2×250 cc). The combined organic phases are washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (4.8 g) is purified by chromatography on a column (height: 30 cm, diameter: 2.8 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (75:25 by volume) (3 liters) of ethyl acetate and cyclohexane and collecting 50-cc fractions. The combined fractions 19 to 50 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-methyl-N-(2-hydroxyethyl)amino]-2-propyl}-2-phenothiazinecarbothioamide (2.2 g) is thereby obtained in the form of a yellow product of meringue-like consistency.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25][C@H:26]2[O:43][C@H:42]([CH2:44][O:45]C(=O)C)[C@@H:37]([O:38]C(=O)C)[C@H:32]([O:33]C(=O)C)[C@H:27]2[O:28]C(=O)C)[C@@H:18]([CH2:49][O:50]C(=O)C)[O:17][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=[O:15])(=O)C>C(N(CC)CC)C.CO.O>[C@H:26]1([O:25][C@@H:19]2[C@@H:18]([CH2:49][OH:50])[O:17][C@@H:6]([S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([OH:16])=[O:15])[C@H:5]([OH:4])[C@H:20]2[OH:21])[O:43][C@H:42]([CH2:44][OH:45])[C@@H:37]([OH:38])[C@H:32]([OH:33])[C@H:27]1[OH:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2C(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1S[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 60.6 %

Procedure:
A solution of 1.6 g of 2-carboxyphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 15 ml of a mixture of 2N triethylamine:methanol:water (3:6:2) was stirred for 16 hours, then concentrated in vacuo to a solid. This solid was dissolved in water, adjusted to pH 3.5, diluted further with water producing a slurry which was applied to 150 ml of a polystyrene resin, for example, Amberlite® XAD-2 resin (Norman Haase) and then eluted with 500 ml of water followed by one liter of 80% methanol. The methanol eluate give 0.6 g of the desired intermediate as a solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH:36]([C:44](O)=O)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[C@H:9]([C:16]([NH:35][CH:36]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:44])=[O:18])[CH2:10]1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(Cc1ccccc1)C(=O)O
Product: CON=C1C[C@@H](C(=O)NC(C)Cc2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and DL-phenylalanine, the title compound was obtained in 62% purity by HPLC. MS(ESI+): m/z=500.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH3:20][Mg]Br.C(OCC)C>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]([OH:9])[CH3:20])[CH3:2]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (0.793 g, 2.95 mmole) in THF (30 mL) at 0° C., is added a solution of methyl magnesium bromide in diethyl ether (3.0M, 2.0 mL, 0.60 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 30 minutes. The reaction is quenched with NH4Cl(aq) (10 mL), partitioned between ethyl acetate (50 mL) and water (50 mL). Extracted the aqueous layer with ethyl acetate (2×50 mL). The combined organic is washed with brine (3×100 mL), dried over Na2SO4, filtered and concentrated to provide the titled compound as a white solid. The crude product is used for the next step without further purification. Mass [EI+] 286 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH:16]2[CH2:18][CH2:17]2)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NC1CC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1NC1CC1

Procedure:
The title compound is prepared from 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 3): tR=1.30 min; Mass spectrum (ESI+): m/z=255 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3][C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18].[OH:21]O>C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[S:3]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])=[O:21]
Reactant: OO
Reactant: O=c1c2ccccc2ccn2cc(SC(F)(F)F)cc12
Solvent: CC(=O)O
Product: O=c1c2ccccc2ccn2cc(S(=O)C(F)(F)F)cc12

Procedure:
A solution of 3gm. of 2-trifluoromethylthio-11H-pyrrolo[2,1-b][3]benzazepin-11-one in 25 ml. of acetic acid containing 3 ml. of 50% hydrogen peroxide is stirred at 25° C. for 6 hrs. The solvent is evaporated and the residue dissolved in 100 ml . of methylene chloride. The solution is washed with 2 × 25 ml. of 5% Na2CO3 solution, dried and evaporated. Chromatography of the residue on silica gel yields 2-trifluoromethylsulfinyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1C=CC=CC=1.[C:15]([C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23])#[N:16].Cl>ClCCl>[Cl:8][C:5]1[S:4][C:3]([NH:2][S:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([C:15]#[N:16])[CH:18]=2)(=[O:25])=[O:26])=[N:7][CH:6]=1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-amino-5-chlorothiazole-hydrochloride (3.76 g, 22.0 mmol) in dichloromethane (20 ml) was added pyridine (8.09 ml, 100 mmol). 3-cyano-4-fluorobenzenesulfonyl chloride (4.39 g, 20 mmol) dissolved in dichloromethane (5 mL) and was added to the reaction mixture dropwise at room temperature. After stirring for 48 hours at room temperature, 1 N HCl (100 mL) was poured into the reaction and the mixture was extracted with dichloromethane/methanol (v/v=95/5, 100 ml) three times. The collected organic layer was evaporated in vacuo and dried over MgSO4 to obtain the crude residue. The crude residue was washed with dichloromethane (10 mL) and filtered to afford pale yellow solid as the title compound. LCMS Rt=1.39 minutes MS m/z 318 [M35ClH]+, 320 [M37ClH]+ 1HNMR (d6-DMSO): δ 7.59 (s, 1H), 7.66-7.73 (m, 1H), 8.15-8.21 (m, 1H), 8.33-8.37 (m, 1H).
Reaction SMILES: [Na].O[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C[O-].[Na+].Cl[CH2:14][C:15](CCl)=[CH2:16]>CO>[CH2:16]([S:9][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)[CH:15]=[CH2:14]
Reactant: C=C(CCl)CCl
Reactant: Oc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccccc1
Yield: 173.8 %

Procedure:
To a 1 L flask at 0 C was added 160 mL of methanol. The solution was kept under 30 C as Na metal (5.10 g, 221.24 mmol) was added in small portions. After all the sodium had reacted, 4-hydroxythiophenol (25.0 g, 2.2 eq) was added to the solution of sodium methoxide. The solution was heated to reflux and 3-chloro-2-chloromethyl-1-propene (11.26 g, 1 eq) was added dropwise over 1 hour. The solution was allowed to reflux overnight. The solution was cooled to 25 C, filtered, and reduced in vacuo to remove the methanol. The crude material was taken up in 500 mL of water and extracted with ether (4×150 mL). The ether layer was washed with 1N HCl, water, brine, and dried over sodium sulfate. The organic layer was reduced in vacuo to a crude orange oil. The oil was purified by flash chromatography 90:10 hexanes/ethyl acetate to yield 23.52 g of a colorless oil. Yield 85.8%. 1H NMR (400 MHz, CDCl3, δ): 7.23 (m, 4H, Ar—H), 6.74 (m, 4H, Ar—H), 5.84 (s, 2H, Ar—OH), 4.70 (s, 2H, C═CH2), 3.57 (s, 4H, CH2); 13C NMR (400 MHz, CDCl3, δ): 155.3 (C1), 140.45 (C10), 138.6 (C5), 134.3 (C8), 132.7 (C4), 126.0 (C7), 116.5 (C3), 116.0 (C6), 40.63 (C11); MS (ESI, m/z): [M+Li]+ calcd for C16H16O2S2, 344.3; found, 344.3.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.C[Li].[CH2:17](OCC)C.[F:22][C:23]1[CH:24]=[C:25]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[F:22][C:23]1[CH:24]=[C:25]([S:31]([N:6]2[CH:7]([CH3:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)(=[O:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1F
Reactant: CCOCC
Agent: [Li]C
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1F
Yield: 44.3 %

Procedure:
The title compound was prepared from phenanthridine (7.17 g, 40 mmol), 1.4 M methyllithium in diethyl ether (29 mL, 40.6 mmol), and 3-fluoro-4-methoxybenzenesulfonyl chloride (8.99 g, 40 mmol) according to the procedure and in the same manner as described in Example 1, step a. The crude product was purified by re-crystallization from a mixture of ethyl acetate-cyclohexane to yield 5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (6.79 g, 17.7 mmol, 44%) as an off-white solid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][CH:13]=[C:14]([C:20](OCC)=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]2[C:3]=1[NH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]2=[O:21]
Reactant: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Temperature: 260 °C
Reaction time: 5.5 h

Procedure:
Compound 6B (2000 g, 5.468 mol) was introduced into the reactor. Dowtherm (4.000 L) was charged to the reactor and degassed at room temperature overnight with nitrogen purge. It was then stirred and warmed to 260° C. EtOH produced was distilled off. The reaction was monitored and was complete after 5.5 h, the reaction was substantially complete. Heat source was removed and the reaction mixture was cooled to 80° C. and heptane (2.000 L) was charged. The mixture was stirred for 30 min. Heptane (6.000 L) was charged to the stirred mixture and stirring continued overnight. Solids were filtered off and washed with heptane (4.000 L) and dried in a vacuum oven at 50° C. to provide Compound 6A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br-:13]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:13][CH:10]([CH3:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(C)Br)cc1
Yield: 90.7 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-methoxy-phenyl)-propan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst. A white solid product was obtained in a yield of 90.7%, mp: 69-70 └. 1H-NMR (CDCl3, 400 MHz) δ: 1.89 (3H, d, J=6.44 Hz, CHBrCH3), 3.88 (3H, s, OCH3), 5.27 (1H, q, J=6.44 Hz, CHBrCH3), 6.96 (2H, d, J=8.72 Hz, ArH), 8.02 (2H, d, J=8.72 Hz, ArH); ESI-MS m/e (%): 242.0 (M+2, 11), 241.0 (M, 11), 135.0 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([I:10])[C:5]([OH:9])=[N:6][C:7]=1[Cl:8].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:9][C:5]1[C:4]([I:10])=[CH:3][C:2]([Br:1])=[C:7]([Cl:8])[N:6]=1)(=[O:13])[CH3:12]
Reactant: Oc1nc(Cl)c(Br)cc1I
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1nc(Cl)c(Br)cc1I
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-bromo-6-chloro-3-iodopyridin-2-ol (12.9 g, 38.6 mmol) was suspended in acetic anhydride (40 mL, 420 mmol) and heated to 110° C. The mixture was heated at this temp for 1 h. After 1 h the reaction mixture appeared as a homogeneous solution. TLC (observed M+H mass in LCMS is primarily of des-OAc) indicated complete reaction. The solution was concentrated azeotroping with toluene (3×25 mL) to give 5-bromo-6-chloro-3-iodopyridin-2-yl acetate (14.5 g, 38.5 mmol, 100% yield) as a tan solid. The solid was taken onto the subsequent Sonogashira coupling without further purification. Observed LCMS reveals mostly hydrolysis product (starting material), but desired mass is present. LCMS: m/e 377 (M+H)+ LCMS retention time: 2.71 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.37 (s, 1H), 2.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:59]([NH2:61])[CH3:60])[CH:55]=[CH:56][C:57]=1[F:58]>C(Cl)(Cl)Cl>[F:51][C:52]1[CH:53]=[C:54]([CH:59]([NH:61][C:43]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[F:1])=[O:49])[CH3:60])[CH:55]=[CH:56][C:57]=1[F:58]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1ccc(F)c(F)c1
Reactant: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)NC(C)c4ccc(F)c(F)c4)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 77.2 %

Procedure:
2-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline (30 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (17 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 25 min. Next, a solution of 1-(3,4-difluorophenyl)ethylamine (14 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 5 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (27 mg, yield 60%).
Reaction SMILES: [Al+3:1].[Cl-:2].[Cl-].[Cl-].[C:5]([O:8]C(=O)C)(=[O:7])[CH3:6]>>[C:5]([Cl:2])(=[O:8])[CH3:6].[C:5]([O-:8])(=[O:7])[CH3:6].[Al+3:1].[C:5]([O-:8])(=[O:7])[CH3:6].[C:5]([O-:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: [Cl-]
Agent: [Al+3]
Product: CC(=O)Cl
Product: CC(=O)[O-]

Procedure:
Advantageously, approximately n equivalents of the carboxylic anhydride, or a slight excess, are used. Naturally, it is also possible, with reduced yield, to use the carboxylic anhydride in less than equivalent amounts. Good results are obtained when 0.95 n to 1.05 n equivalents of the carboxylic anhydride are used. For example, it is possible to react 1 mole of AlCl3 (n=3) with 3 moles of acetic acid anhydride to give acetyl chloride and aluminum acetate.