Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][C:9]([S:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][C:7]=1[CH3:18])=[O:5])[CH3:2].CS(O)(=O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:18][C:7]1[C:8]2[C:15](=[O:17])[CH2:14][CH2:13][S:12][C:9]=2[CH2:10][CH2:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1=C(C)C=C(SCCC(=O)O)CC1
Agent: CS(=O)(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)C2=C(CC1)SCCC2=O
Temperature: 20 °C
Yield: 79.5 %

Procedure:
A mixture of ethyl-4-β-carboxyethylthio-2-methyl-1,3-cyclohexadiene-1-carboxylate (121.3 g, 0.449 mole) in toluene is stirred at 20° C., treated sequentially with 5.0 ml methanesulfonic acid and portionwise over a 5 minute period with trifluoroacetic anhydride (94.3 g, 0.449 mole) and allowed to stir at ambient temperatures for 18 hours. The resultant reaction mixture is quenched with a 1:1 mixture of ethyl acetate and water and stirred for 15 minutes. The phases are separated. The organic phase is washed with water and concentrated in vacuo to give a residue. Crystallization of the residue from isopropanol/heptane affords the title product as a yellow solid, 90.1 g, (79.5% yield), mp 99°-100° C., identified by 1HNMR and mass spectral analyses.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@H:38]1[CH2:41][C@@H:40]([C:42]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:51])[CH3:50].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@H:38]4[CH2:41][C@@H:40]([C:42]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:51])[CH3:50])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) (COCl)2 (0.69 ml, 8.03 mmol) in DCM (4 ml) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(piperidin-1-yl)methanone (Intermediate 12, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4%; δ 5.94 (d, 1H, J=7.8 Hz), 4.74 (s, 1H), 4.59 (s, 1H), 4.54-4.41 (m, 1H), 4.17-4.05 (m, 1H), 3.74-3.62 (m, 1H), 3.37 (brs, 2H), 3.18-3.07 (m, 1H), 2.89 (t, 1H, 7.8 Hz), 2.51-2.40 (m, 1H), 2.39-2.28 (m, 2H), 2.04 (s, 3H), 2.01-1.84 (m, 2H), 1.81-1.75 (m, 1H), 1.74-1.45 (m, 7H), 1.44-1.21 (m, 15H), 1.21-1.09 (m, 2H), 0.95, 0.93 (s, 9H), 0.83-0.82 (m, 12H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm−1): 3372, 2943, 2864, 1736, 1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1192, 1024, 979, 881, 853.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J5) (235 mg, 0.9 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink powder (272 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([NH:28][NH2:29])=O)[CH2:21]1)[CH3:19]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:17][C:26]([CH:22]2[CH2:23][CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21]2)=[N:28][N:29]=1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Reactant: CCN1CCCC(C(=O)NN)C1
Product: CCN1CCCC(c2nnc(-c3nc(-c4cccc(CO)c4)cnc3N)[nH]2)C1

Procedure:
(3-{5-amino-6-[5-(1-ethylpiperidin-3-yl)-4H-1,2,4-triazol-3-yl]pyrazin-2-yl}phenyl) methanol was prepared from 3-amino-6-[3-(hydroxymethyl) phenyl]pyrazine-2-carbonitrile and 1-ethyl piperidine-3-carbohydrazide in a manner analogous to that described in the previous example: 1H NMR (400 MHz; DMSO-d6): 8.8 (s, 1H); 8.15 (s, 1H); 8.15 (s, 1H); 8.07 (d, 1H); 7.7 (br s, 1H); 7.47 (t, 1H); 7.4 (t, 1H); 5.25 (t, 1H); 4.6 (d, 2H); 3.1-2.9 (m, 3H); 2.4 (m, 2H); 2.2-1.9 (m, 3H); 1.8-1.6 1 (m, 3H); 1.04 (t, 3H); MS (EI) for C20H25N7O: 380 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][C:21]2[CH:35]=[CH:34][C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][C:21]2[CH:35]=[CH:34][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed tert-butyl 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)phenoxy]acetate (200 mg, 0.33 mmol, 1.00 equip, 98%), trifluoroacetic acid (379 mg, 3.32 mmol, 10.00 equip), and dichloromethane (20 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was purified by re-crystallization from methanol to yield 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)phenoxy]acetic acid as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1OS(C)(=O)=O)(=[O:4])=[O:3].[N-:20]=[N+]=[N-].[Na+]>CC(N(C)C)=O.CCOC(C)=O>[NH2:20][C@@H:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1N
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
(1R,2S)-1-Methanesulphonamido-2-methylsulphonyloxyindan (2.0 g, 6.56 mmol) was dissolved in dry dimethyl acetamide (20 ml). Sodium azide (1.7 g, 26.2 mmol) was added and the mixture heated to 90° C. for 1 hour. The reaction was cooled, diluted with EtOAc (100 ml), washed with water (6×50 ml), dried over magnesium sulphate and filtered. 10% Palladium on activated carbon was added and the mixture stirred under a hydrogen atmosphere for 3 hours. Filtration through celite followed by evaporation gave the title compound (1.25 g, 83%) as a pale green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Temperature: 35 °C
Yield: 95.7 %

Procedure:
Methyl 5-chloro-2-(3-phenoxyazetidin-1-yl)nicotinate (D75) (305 mg, 0.96 mmol) was dissolved in methanol/tetrahydrofuran (10 ml/10 ml), 5N NaOH (10 ml) was added at 0° C. The resulting reaction mixture was heated to 35° C. for 18 hours then cooled to room temperature and concentrated. Water added (10 ml) and the mixture was acidified with 2.5N HCl (pH1-2). The white solid was collected, washed with water and dried to provide compound (D101) (280 mg) as a white solid.
Reaction SMILES: Cl[C:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Si](C)(C)C)=[N:19][CH:20]=1>CCCCCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]([C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[N:19][CH:20]=1
Reactant: C[Si](C)(C)c1ccc(Br)cn1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: CCCCCC
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2ccc(Br)cn2)CC1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a flask containing methyl trans-4-(chlorocarbonyl)cyclohexanecarboxylate (8.19 g, 40 mmol) was added 5-bromo-2-(trimethylsilyl)pyridine (8.4 g, 36.4 mmol). The resulting mixture was heated to 110° C. for 10 hours. The reaction was allowed to cool to 70° C., and hexane (30 mL) was added dropwise. The resulting mixture was stirred for 14 hours at room temperature, filtered, and the residue was washed with hexane (20 mL). The beige solid was dried under nitrogen to afford methyl trans-4-[(5-bromopyridin-2-yl)carbonyl]cyclohexanecarboxylate. MS ESI calcd for C14H17BrNO3 [M+H]+ 326 and 328. found 326 and 328. 1H NMR (600 MHz, CDCl3) δ 8.70 (d, J=1.8 Hz, 1H), 7.94 (dd, J=8.4, 2.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 3.78 (tt, J=11.9, 3.4 Hz, 1H), 3.66 (s, 3H), 2.32 (tt, J=12.2, 3.6 Hz, 1H), 2.08 (dd, J=13.8, 3.5 Hz, 2H), 1.99 (dd, J=13.9, 3.1 Hz, 2H), 1.60 (m, 2H), 1.45 (m, 2H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[I:11].N([O-])=O.[Na+].[ClH:16]>O.Cl[Cu]>[Cl:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[I:11]
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(I)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-amino-5-nitro-iodobenzene (10.00 g, 37.9 mmol) was suspended in 12 N HCl (25 mL) and water (40 mL) and stirred for 30 min at 22° C. The mixture was then cooled to 0° C. and NaNO2 (5.23 g, 75.8 mmol in 18 mL of H2O) was added over a 10 min period. After 1 h, this solution was transferred to a solution of CuCl (3.75 g, 37.9 mmol) in water (50 mL) at 60° C. After 2 h, the mixture was cooled to 22° C. and extracted with EtOAc (3×150 mL) and the organics were dried over anhydrous MgSO4. The crude product was purified by silica gel flash chomatography eluting with 10-20% CH2Cl2 in hexanes to give compound 801A (4.20 g) as a yellow solid. HPLC: 100% at 3.447 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:19]([O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])[C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:8]=2[CH:18]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]([O:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:20])[C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][C:8]=2[CH:18]=1
Reactant: O=C(OCCN1CCCCC1)c1cc([N+](=O)[O-])cc2cc(-c3ccccc3)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)OCCN2CCCCC2)c2oc(-c3ccccc3)cc2c1
Yield: 71.8 %

Procedure:
A mixture of 1.5 g of 2-piperidinoethyl 5-nitro-2-phenylbenzofuran-7-carboxylate, 4.29 g of stannous chloride dihydrate and 100 ml of ethyl acetate is heated at 70°-80° C. for 2 hours. The reaction mixture is neutralized with an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove solvent. The residue is recrystallized from isopropanol to give 995 mg of 2-piperidinoethyl 5-amino-2-phenylbenzofuran-7-carboxylate as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[C:23]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1

Procedure:
Preparation analogously to Example 37 from 9-amino-5-oxo-6-benzyl-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and propionic acid chloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]([OH:5])[CH3:4].[C:7](O)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][CH:3]([O:5][C:7](=[O:11])[CH:8]=[CH:9][CH3:10])[CH:2]([CH3:6])[CH3:1]
Reactant: C/C=C/C(=O)O
Reactant: CC(C)C(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)C(C)C
Yield: 52.4 %

Procedure:
3-Methyl-butan-2-ol (180 g), crotonic acid (165 g), toluene (200 mL), and PTSA (8 g) were charged into to a 2-L reaction flask fitted with a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged at reflux for about 13-15 hours till GC analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with brine, sodium carbonate, and brine, and further purified by fractional distillation to provide but-2-enoic acid 1,2-dimethyl-propyl ester (157 g) with a boiling point of 53° C. at 0.77 mmHg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=4)[C:28](=[O:39])[N:27]([CH3:40])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[C:35]([CH2:37][CH3:38])[O:34][N:33]=4)[C:28](=[O:39])[N:27]([CH3:40])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 158c (190 mg, 0.35 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added NaBH4 (26.5 mg, 0.70 mmol). The reaction mixture was stirred at room temperature for 1 h and quenched with aqueous NH4Cl. It was then concentrated under reduced pressure and the residue was extracted with dichloromethane. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 158 (70 mg, 37%) as white solid. MS-ESI: [M+H]+ 545.3. 1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=13 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.26 (s, 1H), 4.90 (s, 1H), 4.44-4.43 (m, 2H), 3.61 (s, 3H), 2.69-2.65 (m, 2H), 1.40 (s, 9H), 1.19 (t, J=8.0 Hz, 3H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([CH2:12][N:13]([CH2:32][CH:33]3OCCO3)[C:14]([C:16]3[NH:17][CH:18]=[C:19]([C:21](=[O:31])[C:22]4[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=4[F:30])[CH:20]=3)=[O:15])[N:11]=[C:5]2[CH:4]=1)#[N:2].CS(O)(=O)=[O:40]>CC#N.O>[O:15]=[C:14]1[C:16]2[NH:17][CH:18]=[C:19]([C:21](=[O:31])[C:22]3[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=3[F:28])[C:20]=2[CH:33]=[CH:32][N:13]1[CH2:12][C:10]1[N:11]=[C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:40])[CH:8]=[CH:7][N:6]2[CH:9]=1
Reactant: N#Cc1ccn2cc(CN(CC3OCCO3)C(=O)c3cc(C(=O)c4c(F)cc(F)cc4F)c[nH]3)nc2c1
Reactant: CS(=O)(=O)O
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Temperature: 95 °C

Procedure:
The product from step B (430 mg, 0.884 mmol) was dissolved in methanesulfonic acid (2.0 mL) and heated to 95° C. in an oil bath for 25 min. After cooling in an ice-water bath, the reaction mixture was diluted with 2:3 MeCN—H2O (3 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (174 mg). LC/MS: m/z 467(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.46 (s, 2H), 7.01 (d, 1H), 7.33 (t, 2H), 7.58-7.59 (m, 2H), 7.61 (s, 1H), 7.79 (s, 1H), 7.91 (d, 1H) 8.12 (d, 1H), 8.33 (s, 1H), 8.72 (d, 1H), 13.12 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: COC[C@H](C)Oc1cc(OCc2cccs2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3cccs3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(thiophen-2-ylmethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[C:18]([C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:23]=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(C#N)c3)cc2C1

Procedure:
The title compound was prepared from N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide and 3-cyanophenyl boronic acid in a similar manner to Example 1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:28]=2[F:27])[CH:7]=1
Reactant: OCc1cc(F)cc(F)c1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)cc(F)c3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,3,5-trifluorobenzyl alcohol (119 mg; 0.736 mmol), example 84 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: CCOCC.Br[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>[Cl-].[Na+].O>[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Brc1cccs1
Reactant: Cc1ccnc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(-c2cccs2)nc2ccccc12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A two necked round-bottom flask (250 mL) containing a stir bar fitted with a reflux condenser was evacuated and purged with nitrogen gas. Dry ether (50 mL) and 2-bromothiophene (0.0191 mol, 3.06 g) was added to the flask followed by the slow addition of n-BuLi (0.0229 mol, 9.17 mL) via a syringe pump. The reaction mixture was stirred at room temperature for 30 min to 40 min and then 4-methylquinoline (0.0191 mol, 2.72 g) was slowly added. The reaction mixture was refluxed for an additional 2 to 3 hr. The reaction mixture was then cooled to room temperature and diluted with an aqueous brine solution and extracted with ether (3×30 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using hexanes/CH2Cl2 as eluent to afford 2.77 g of 4-methyl-(2-thiophenyl)quinoline (65% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13]/[C:14](/[CH3:23])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:22])=[CH:19]/[CH2:20][OH:21])/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[S:32])[CH:25]=1>C1COCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[S:32])[O:21][CH2:20]/[CH:19]=[C:18](\[CH3:22])/[CH2:17][CH2:16]/[CH:15]=[C:14](\[CH3:23])/[CH2:13][CH2:3]/[CH:4]=[C:5](\[CH3:6])/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:25]=1
Reactant: S=C=Nc1cccnc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of NaH (60% dispersed in oil, 32 mg, 0.81 mmo) in THF (4 mL) at 0° C. was added alcohol 1 (180 mg, 0.62 mmol) in THF (1 mL) and the reaction mixture was stirred for 30 min at this temperature. Then 3-pyridyl isothiocyanate (169 mg, 124 mmol) in THF (1 mL) was added and stirred at rt. After stirring for 12 h, the reaction mixture was quenched water and extracted with EtOAc (3×). The organic layer was dried and concentrated to get a residue, which was purified by column chromatography (Hexane/EtOAc) to yield thiocarbamate 38a as a viscous liquid (179 mg, 70%). TLC Rf: 0.23 (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): δ 8.55 (d, 1H), 8.40 (d, 1H), 7.95 (m, 1H), 7.30 (m, 2H), 5.49 (t, 1H), 5.11 (m, 3H), 4.70 (d, 2H), 2.16-1.19 (m, 12H), 1.76 (s, 3H), 1.68 (s, 3H), 1.60 (s, 9H); LCMS: MS (m/z): 427 (M+H).