Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:15]=1[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C([O-])(O)=O.[Na+].N#N>O1CCOCC1.O.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]>[NH2:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][C:15]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:14]=2[F:13])=[C:18]([C:2]2[N:7]3[CH:8]=[N:9][CH:10]=[C:6]3[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=2)[CH:19]=1
Reactant: Cn1cc(Br)n2cncc2c1=O
Reactant: CC1(C)OB(c2cc(N)ccc2Oc2ccc(F)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Yield: 59.7 %

Procedure:
A solution of 5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one (114.0 mg, 0.5 mmol), the title compound of Example 57, step 1 (208.0 mg, 0.6 mmol), Pd(dppf)2Cl2 (37.0 mg, 0.05 mmol), NaHCO3 (126.0 mg, 1.5 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred in microwave at 110° C. with N2 atmosphere for 3 hours. The solvent was evaporated to give the crude product, which was purified by column chromatography (PE:EA=3/1) to give the title compound (110 mg, 60%) as a yellow solid. 1H NMR (CDCl3 400 MHz) δ 7.94 (s, 1H), 7.82 (s, 1H), 6.93-6.82 (m, 2H), 6.79-6.74 (m, 4H), 6.41 (s, 1H), 3.50 (s, 3H). LCMS (M+H)+ 369.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+]>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:21])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[N:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 5 h

Procedure:
4.38 g (25.0 mmol) of 2-chloro-4,6-dimethoxy-pyrimidine and 4.68 g (26.3 mmol) of sodium p-toluenesulfinate were heated in 25 ml of N,N-dimethylformamide to 100° C. while stirring. After 5 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was taken up in 90 ml of water and 90 ml of ethyl acetate. After the organic phase had been separated off, the aqueous phase was again extracted with 75 ml of ethyl acetate. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column (eluent hexane/ethyl acetate 4:1). The title product was obtained from the product fraction in the form of a white powder in a yield of 3.79 g (15 percent of theory). The melting point of the title compound was 129.2° to 133.4° C. Other data concerning the title compound was:
Reaction SMILES: [CH:1]1C=CC(C([C@H]2OCC(NCCC3C=CC(F)=CC=3)C(O)C2)C2C=CC=CC=2)=CC=1.[CH2:31]([O:35][C:36]([C:38]1[N:39]=[C:40](Cl)[C:41]2[C:46]([C:47]=1[OH:48])=[CH:45][CH:44]=[C:43]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[CH:42]=2)=[O:37])[CH2:32][CH2:33][CH3:34]>>[CH2:31]([O:35][C:36]([C:38]1[N:39]=[C:40]([CH3:1])[C:41]2[C:46]([C:47]=1[OH:48])=[CH:45][CH:44]=[C:43]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[CH:42]=2)=[O:37])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2c1O
Reactant: OC1C[C@@H](C(c2ccccc2)c2ccccc2)OCC1NCCc1ccc(F)cc1
Product: CCCCOC(=O)c1nc(C)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2c1O

Procedure:
Prepared in analogy to Example D-157 d) from 4-hydroxy-1-chloro-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (of Example D-92 f). MS-(+)-ion M+1=420.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([OH:34])[CH2:29][CH2:30][CH2:31][C:32]#[CH:33]>COCCOC.O.[Pd].[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:34][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: C#CCCCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(C#CCCCCO)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 5-bromo-3-(1-tert-butoxycarbonyl-2(S)-pyrrolidinylmethoxy)pyridine (800 mg, 2.24 mmol), K2CO3 (745 mg, 5.40 mmol), PPh3 (55 mg) in DME (4 mL) and H2O (4 mL) was added 10% Pd/C (55 mg) and CuI (55 mg). The mixture was stirred at room temperature for 30 ml under argon, then 5-hexyn-1-ol (1.0 mL) was added. The reaction mixture was refluxed for 72 h. After cooled, the mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by chromatography with hexane-EtOAc (1:1) to give an oil (800 mg, 95%), [α]D=−35.5 (c 2.2, CHCl3). 1H NMR (CDCl3) δ 8.19 (m, 2H), 7.23 (m, 1H), 4.14 (m, 2H), 4.05-3.75 (m, 1H), 3.75-3.69 (m, 2H), 3.50-3.25 (m, 2H), 2.47 (t, 2H, J=6.6 Hz), 2.10-1.64 (m, 9H), 1.47 (s, 9H); 13C NMR (CDCl3) δ154.70, 154.36, 144.76 and 144.49, 137.29 and 137.00, 123.04, 121.15, 93.32, 79.96 and 79.56, 68.69 and 68.33, 62.28, 55.94 and 55.64, 46.97 46.59, 31.82, 28.51, 28.00, 24.79, 23.84, 22.83, 19.20.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:26])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.O.[OH-].[Li+].Cl>CO>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:27])=[O:2])=[O:26])=[CH:13][CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1C(=O)O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
To 2-(4-benzyloxy-benzoylamino)-benzoic acid methyl ester (50 mg) in methanol (3 mL) was added lithium hydroxide monohydrate (6.3 mg) and the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then reacidified using 1N HCl and the product was then purified by column chromatography (SiO2, ethyl acetate-ethanol: 0-20%) to give 2-(4-benzyloxy-benzoylamino)-benzoic acid as a white solid (39 mg). MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([N:15]([CH3:17])[CH3:16])=O)=[CH:2]1.B.CO.C(O)(=O)C(O)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[CH2:13][N:15]([CH3:17])[CH3:16])=[CH:2]1
Reactant: CN(C)C(=O)c1ccccc1Sc1c[nH]c2ccccc12
Agent: B
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1ccccc1Sc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(1H-Indol-3-ylsulfanyl)-N,N-dimethyl benzamide (1 mmol) was dissolved in dry tetrahydrofuran (30 mL). To the mixture was added 3 mL 1 M borane in tetrahydrofuran and the mixture was stirred at room temperature for 24 hours. Methanol (5 mL) was added and the mixture stirred at room temperature for 30 min and then evaporated in vacuo. The mixture was redissolved in ethyl acetate (100 mL) and washed with saturated sodium hydrogen carbonate (20 mL), dried over anhydrous MgSO4 and evaporated in vacuo. The product was crystallized as an oxalate salt by dissolution in acetone and addition of one equivalent of oxalic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1ccc2ccccc2n1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc3ccccc3n2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Quinoline-2-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=488.4.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[S:12])([CH3:3])[CH3:2].Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([CH:15]1[S:12][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[N:13][C:16]1=[O:17])[CH3:20]
Reactant: CCC(Br)C(=O)O
Reactant: CC(C)c1ccccc1NC(N)=S
Product: CCC1SC(Nc2ccccc2C(C)C)=NC1=O

Procedure:
Synthesis was performed from N-(2-isopropylphenyl)thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[C:10]([C:11](O)=[O:12])=[CH:9][C:8]([CH3:14])=[N:7]1>CN(C)C=O>[CH3:5][N:6]1[C:10]([C:11]([Cl:3])=[O:12])=[CH:9][C:8]([CH3:14])=[N:7]1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.04 ml, 14.4 mmol) is added to a stirred solution of 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.5 g, 3.6 mmol) and dimethylformamide (3 drops). The reaction is stirred for 2 hours at room temperature and then for 2 hours at 80° C. The reaction is concentrated. The residue is dissolved in dichloromethane and then the solvent is evaporated to yield 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[OH:10].[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([I:12])[CH:7]=[N:6][C:5]=1[OH:10]
Reactant: COC(=O)c1cccnc1O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: COC(=O)c1cc(I)cnc1O
Yield: 82.3 %

Procedure:
To a solution of 2-hydroxynicotinic acid methyl ester (3-067-02) (20 g) in methylene chloride (500 mL) was added N-iodosuccinimide (NIS, 38 g) at room temperature, and the reaction mixture was heated under reflux for 16 h, and evaporated. To the residue was added ethyl acetate (200 mL) and the reaction mixture was heated under reflux for 2 h. The insoluble solid was filtered to give 2-hydroxy-5-iodonicotinic acid methyl ester (3-067-03) (30 g, 81%) as a white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][N:13]=[C:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=3[F:30])[CH2:16][CH2:15]2)[CH2:8][CH2:7]1.[N:31]#[C:32]Br.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O>[F:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=[CH:25][C:20]=1[N:17]1[CH2:18][CH2:19][C:14](=[N:13][O:12][CH:9]2[CH2:10][CH2:11][N:6]([C:32]#[N:31])[CH2:7][CH2:8]2)[CH2:15][CH2:16]1
Reactant: N#CBr
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(C#N)CC3)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To sodium bicarbonate (34 mg, 0.4 mmol), was added water (17 μL) and 63a (74 mg, 0.2 mmol) in 1 mL of DCM. The mixture was cooled to 0° C. and cyanogen bromide (25 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. Sodium carbonate was added as well as magnesium sulfate and the solids were filtered and rinsed with DCM. The filtrate was concentrated to give 107 mg of 68b.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:11][CH2:12][O:13][C:14]([CH:16](P(OCC)(OCC)=O)[CH3:17])=[O:15].C[O-].[Na+]>CN(C=O)C.CO>[OH:10][CH2:9][C:7]1[N:8]=[C:3](/[CH:2]=[C:16](\[CH3:17])/[C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1cccc(CO)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)/C(C)=C/c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
6-hydroxymethylpyridine-2-carbaldehyde (2.95 g) and triethyl 2-phosphonopropionate (5.12 g) were dissolved in 20 mL of dry DMF, and to the solution was added a solution of 1.30 g of sodium methoxide in 10 mL of methanol dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was thrown into ice-water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=1:1) to give 2.42 g of ethyl (E)-3-(6-hydroxymethylpyridin-2-yl)-2-methylacrylate as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:23])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:22])=[C:13]([S:19]C#N)[C:14]=2[CH3:18])[O:9]1.O.Cl>CCOCC>[CH3:7][C:8]1([CH3:23])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:22])=[C:13]([SH:19])[C:14]=2[CH3:18])[O:9]1
Reactant: Cc1cc2c(c(C)c1SC#N)CCC(C)(C)O2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(c(C)c1S)CCC(C)(C)O2
Temperature: 15 °C

Procedure:
Lithium aluminum hydride (2.65 g, 69.6 mM) was suspended in anhydrous ether (165 ml) under an atmosphere of argon with external cooling to 15° C. A solution of the thiocyanate (A) (8.6 g, 34.8 mM) in anhydrous ether (100 ml) was added dropwise during 30 minutes and the mixture was then heated under reflux for 30 minutes. The reaction mixture was cooled and ether (80 ml) was added. Water (80 ml) was then added cautiously dropwise followed by 2M hydrochloric acid (120 ml). The organic layer was separated and combined with a further extract. The combined organic phase was washed with saturated sodium bicarbonate solution and then with brine. Evaporation of the solvent gave 2,2,5,7-tetramethylchroman-6-thiol (B) as a clear oil which was used without further purification.
Reaction SMILES: C([O:5][C:6]1[C:11]([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])([CH3:19])[CH2:15][CH2:14]2)=[N:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][C:16]1([CH3:19])[CH2:17][CH2:18][N:13]([CH2:12][C:11]2[C:6](=[O:5])[NH:7][CH:8]=[CH:9][N:10]=2)[CH2:14][CH2:15]1
Reactant: CC1(COc2ccccc2Cl)CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(COc2ccccc2Cl)CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 1 h
Yield: 51 %

Procedure:
After dissolving 237 mg of 2-tert-butoxy-3-[4-(2-chlorophenoxymethyl)-4-methylpiperidino]methyl-pyrazine in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added while stirring on ice. After 1 hour, aqueous sodium carbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the precipitate was filtered out to obtain the title compound (104 mg, 51% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[F:23][C:24]1[N:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(F)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-fluoropyridine-5-boronic acid pinacol ester (125 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(6-fluoropyridin-3-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.5 (s, 1H), 8.21 (dd, 1H), 7.72 (m, 2H), 7.62 (s, 1H), 7.5 (d, 1H), 7.3 (s, 1H), 7.17 (m, 2H), 7.06 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.56 (m, 1H), 3.21 (m, 1H), 3.18 (s, 3H), 3.1 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH:21]=[C:22]4[C:26]=3[CH2:25][NH:24][C:23]4=[O:27])=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH:21]=[C:22]4[C:26]=3[CH2:25][NH:24][C:23]4=[O:27])=[CH:16][CH:17]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3cc(OCC(=O)OC(C)(C)C)cc4c3CNC4=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cc(OCC(=O)O)cc4c3CNC4=O)cc2)c1

Procedure:
A solution of Example 105B (70 mg, 0.14 mmol) in TFA (4 mL) was stirred at room temperature for 4 hours, then concentrated to give the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H); 4.44 (s, 2H); 4.83 (s, 2H); 6.80 (d, J=7.7 Hz, 1H); 7.08 (d, J=2.4 Hz, 1H); 7.17 (t, J=7.7 Hz, 1H); 7.20 (d, J=2.4 Hz, 1H); 7.25 (d, J=8.7 Hz, 1H); 7.31 (s, 1H); 7.56 (m, 4H); 8.65 (s, 1H); 8.64 (s, 1H); 8.82 (s, 1H), 12.45–13.70 (br. s, 1H); MS (ESI(−)) m/e 430.1 (M−H)−.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].COC(SCl)=O.[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(Cl)Cl>[CH:18]1[CH:19]=[C:14]([S:13][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[N:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CCS
Reactant: Sc1ccccn1
Agent: COC(=O)SCl
Solvent: ClCCl
Product: O=C(O)CCSSc1ccccn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
5.00 g (52.2 mmol) of 3-mercaptopropanoic acid (Aldrich Chemical Co., Milwaukee, Wis.) in 75 ml of dry methylene chloride was added to a solution of 5.96 g (52.2 mmol) of methoxycarbonylsulfenyl chloride (Fluka Chemika, Long Island, N.Y.) in 150 ml of dry methylene chloride. The mixture was stirred at 15-25° C. for 90 minutes and then concentrated. The residue was redissolved in 150 ml of dry methylene chloride and dropwise treated with 5.80 g (52.2 mmol) of 2-mercaptopyridine (Aldrich Chemical Co.) in 75 ml of dry methylene chloride. The mixture was stirred at 15-25° C. for 18 hours and concentrated to afford 11.2 g of the product as a pale yellow oil (99%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4OC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4OC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methoxy-3-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.48 g) in methylene chloride (14.4 ml) was added dropwise a solution of m-chloroperbenzoic acid (187 g) in methylene chloride (9.6 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and recrystallized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methoxy-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 249) (267 mg).
Reaction SMILES: ClC1C=C(/C=C/C(N2CCC(=O)NCC2)=O)C=CC=1Cl.Cl.Cl.[N:23]1([CH2:29][CH2:30][CH2:31][N:32]2[C:38](=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl:40][C:41]1[CH:51]=[CH:50][C:44](/[CH:45]=[CH:46]/[C:47](O)=[O:48])=[CH:43][C:42]=1[F:52]>CCOC(C)=O>[Cl:40][C:41]1[CH:51]=[CH:50][C:44](/[CH:45]=[CH:46]/[C:47]([N:35]2[CH2:36][CH2:37][C:38](=[O:39])[N:32]([CH2:31][CH2:30][CH2:29][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:33][CH2:34]2)=[O:48])=[CH:43][C:42]=1[F:52]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Agent: Cl
Agent: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(Cl)c(F)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 1A, 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and (E)-4-chloro-3-fluorocinnamic acid gave after work up with EtOAc (×3)/saturated NaHCO3 and precipitation (n-pentane) the title compound as off-white solid. MS: 422.2 (MH+, Cl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH3:14])[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[CH:17]=1)#[N:2].C([O-])([O-])=[O:23].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:23])=[C:4]([NH:15][C:16]2[S:20][N:19]=[C:18]([CH3:21])[CH:17]=2)[CH:5]=1)[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2cc(N[C@H](C)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](C)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (127 mg, 0.421 mmol) in DMSO (2 mL), K2CO3 (200 mg, 1.45 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 100 C for 5 min, the mixture was purified by HPLC to give the titled compound (34 mg). MS 320.3 (M+H); UV 205.3, 294.6 nm