Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3cccc(OC)c3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (75% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 25 mg (0.17 mmol, 1.1 eq.) of 3-methoxybenzoic acid were reacted according to General Method 1. Yield: 47 mg (72% of theory)
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[CH3:12][CH:13]1[NH:14][CH2:15][CH2:16][N:17]([C:9]([C:6]2[NH:5][C:4]3[CH:3]=[CH:2][S:1][C:8]=3[CH:7]=2)=[O:11])[CH2:18]1
Reactant: O=C(O)c1cc2sccc2[nH]1
Reactant: CC1CNCCN1
Product: CC1CN(C(=O)c2cc3sccc3[nH]2)CCN1
Yield: 78 %

Procedure:
4H-Thieno[3,2-b]pyrrole-5-carboxylic acid (50 mg, 0.30 mmol) was coupled with 2-methylpiperazine according to Procedure D to provide the title compound (58 mg, 78%) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.15. MS (electrospray): exact mass calculated for C12H15N3OS, 249.09; m/z found, 250.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): 7.33 (d, J=5.3 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.88 (s, 1H), 4.62-4.56 (m, 2H), 3.50-3.20 (m, 5H), 1.36 (d, J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:8]1([C:4]2[N:3]=[C:2]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[CH:22]4)[CH:7]=[N:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: Brc1cncc(C2CC2)n1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)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: [Na+]
Solvent: C1COCCO1
Product: c1cc2[nH]ncc2cc1-c1cncc(C2CC2)n1
Temperature: 100 °C
Yield: 45.6 %

Procedure:
A reaction vessel was charged with 2-bromo-6-cyclopropylpyrazine (1.27 g, 6.39 mmol, Combi-Phos Catalysts Inc.) and Pd(PPh3)4 (308 mg, 0.27 mmol). The tube was sealed. A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.30 g, 5.33 mmol) in dioxane (18 mL) and 2 M Na2CO3 (aq.) (8.0 mL, 16.0 mmol) were added. The reaction was stirred and heated at 100° C. overnight. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-1H-indazole (575 m g, 2.43 mmol, 46% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 237.2 (M+1).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:2]1[CH2:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:1]1)[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCSc2ccccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CC(=O)c2ccccc2S1
Yield: 48 %

Procedure:
A solution of 23.9 g of 4-thiochromanone, 30 ml of 3-buten-2-ol and 240 mg of p-toluenesulfonic acid in 30 ml of 2,2-dimethoxy-propane and 240 ml of anhydrous toluene was boiled under reflux for 20 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 15.3 g (48%) of (RS)-2-(2-buten-1-yl)-4-thiochromanone were obtained as a yellow oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([O:13]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:30]#[N:31].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:29][N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]3[C:18](=[C:30]([NH2:31])[C:10]([C:11]([N:16]=3)=[O:13])=[C:2]3[NH:1][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:3]3)[CH:19]=2)[CH2:28][CH2:27]1
Reactant: CN1CCN(c2ccc(N)c(C#N)c2)CC1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN1CCN(c2ccc3c(c2)=C(N)C(=C2Nc4ccccc4N2)C(=O)N=3)CC1
Temperature: 80 °C

Procedure:
Ethyl 2-benzimidazol-2-ylacetate (1.1 eq) and 2-amino-5-(4-methylpiperazinyl)benzenecarbonitrile (1.0 eq) were dissolved in 1,2-dichloroethane, and then SnCl4 (11 eq) was added. The mixture was heated at reflux overnight. Upon cooling, the mixture was concentrated in vacuo. NaOH (3 M) was added to the solid, and the mixture heated at 80° C. for 0.5 hours. The solid was filtered and washed sequentially with H2O, CH2Cl2, and acetone. LC/MS indicated that the product was present in the acetone layer and the solid. These fractions were combined and purified by silica gel chromatography (5-10% MeOH in CH2Cl2 with 1% Et3N) to give the desired product. LC/MS m/z 375.4 (MH+), Rt 1.65 minutes.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[C:13]([F:25])[CH:12]=1)[CH3:2].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[C:29](Cl)[N:28]=1>>[CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:29]3[C:30]([Cl:34])=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[N:28]=3)[CH2:21][CH2:20]2)=[O:18])=[C:13]([F:25])[CH:12]=1)[CH3:2]
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)c(F)c1
Yield: 84.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (387 mg) described in Preparation Example 160 and 2,3,5,6-tetrachloropyridine (358 mg), the title compound (495 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[I:38]I>C1C=CC=CC=1.S([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][I:38])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)CCc1ccc(CO)cc1C
Reactant: II
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(CI)cc1C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) and dichloromethane (10 mL) is stirred at room temperature. A solution of iodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the black mixture is stirred at room temperature 2 hr. The brown mixture is diluted with 10% aqueous sodium hydrogen sulfite (5 mL) and the resulting clear mixture is washed with ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 9:1 hexanes:ethyl acetate to afford the title compound as a crystalline ivory solid, 0.689, 72%. MS M++1 319. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:10]([CH3:15])[C:11]([Cl:14])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:10]([CH3:15])[C:11]([Cl:14])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)n2C)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)n1C
Yield: 9 %

Procedure:
Seven grams of ethyl 1,4-dimethyl-5-(1-methyl-5'-chloropyrrol-2-oyl)pyrrole-2-acetate (0.23 mole) is hydrolyzed with 25 ml 10% NaOH solution at room temperature. After acidifying and extracting with methylene chloride, the crude product is crystallized upon removal of solvent to give 6.1 g (90%) of crystalline 1,4-dimethyl-5-(1-methyl-5'-chloropyrrol-2-oyl)pyrrole-2-acetic acid, m.p. 148°-149° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][N:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15]1>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][N:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CC(c2ccccc2)c2ccccc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CC(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of p-toluenesulfonyl chloride (102.2 g) in pyridine (140 ml) was added dropwise at 5°-10° to 2,3-dihydro-1-(hydroxyimino)-3-phenyl-1H-indene (60 g) in 270 ml pyridine. The reaction mixture was then stirred for 8 hours at room temperature, poured into ice-water to separate out the title compound, which was filtered, washed several times with water, then once with ether, and finally dried in air. Yield: 96.5 g; m.p. 123°-127°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15]>O1CCCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Temperature: -78 °C
Yield: 65.7 %

Procedure:
A solution of 1-methyl-1H-[1,2,3]triazole (350 mg) in dry tetrahydrofuran (5.0 ml) was added dropwise under nitrogen to a stirred, cooled (-78° C.) solution of n-butyl lithium (2.81 ml of 1.6M solution in hexanes) in dry tetrahydrofuran (10 ml). After 1 hour tributylchlorostannane (1.46 g) was added. The reaction was maintained at -78° C. for 30 min. and then allowed to warm to room temperature over 2 hours. The reaction mixture was diluted with brine (10 ml) and extracted into ethyl acetate (50 ml). The organic layer was separated, washed with brine (50 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (20% ethyl acetate/n-hexane), to give 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole as a yellow oil (1.03 g). 1H NMR (360 MHz,CDCl3) δ 0.87 (9H, m), 1.15 (6H, m), 1.28 (6H, m), 1.36 (6H, m), 4.02 (3H, s), 7.60 (1H, s); MS m/z CI+ 372 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1ccccc1CBr

Procedure:
A mixture of 2-methylbenzophenone (9.8 g), N-bromosuccinimide (8.9 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (150 ml) was refluxed for 1 hour with light irradiation. The mixture was cooled, and then filtered to remove insoluble substances. The filtrate was concentrated to afford quantitatively the above-titled compound as an oily susbstance.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)(=O)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].Cl>>[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([OH:1])=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 80 °C
Yield: 103 %

Procedure:
5M NaOH (4 mL, 20 mmol) was added to 7-(3-tert-Butoxymethyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (0.398 g, 1.11 mmol) and the reaction was stirred and heated at 80° C. for 2 hours. The reaction was let cool to room temperature and HCl (−2 mL) was then added dropwise to the reaction mixture to precipitate the product (pH 1), which was filtered immediately and washed with water and dried in vacuo to afford 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (340 mg, 100%) as a brown solid. 1H-NMR (DMSO-d6): 8.64 (s, 1H), 8.21 (d, 1H, J=7.59 Hz), 8.14 (s, 1H), 7.31 (t, 1H, J=7.59 Hz), 7.18 (d, 1H, J=7.59 Hz), 6.88 (s, 1H), 6.56 (s, 1H), 4.47 (s, 2H), 1.25 (s, 9H).
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[ClH:7].[CH2:8]([OH:10])[CH3:9]>>[ClH:7].[CH3:4][CH:3]([CH3:5])[CH2:2][C:1](=[NH:6])[O:10][CH2:8][CH3:9]
Reactant: CCO
Reactant: CC(C)CC#N
Agent: Cl
Product: CCOC(=N)CC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Isovaleronitrile (2.0 g, 24.1 mmol) was dissolved in anhydrous ethanol (48 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 3-methylbutanimidate hydrochloride (4.0 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.00 (br s, 1H), 11.09 (br s, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.48-2.47 (m, 2H), 2.02-2.01 (m, 1H), 1.33 (t, J=7.0 Hz, 3H), 0.91 (d, J=6.7 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:23]2[C:24]([F:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=2[Cl:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)c2ccccc2)C1
Reactant: Oc1c(F)ccc(F)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2c(F)ccc(F)c2Cl)c2ccccc2)C1
Yield: 91.5 %

Procedure:
A mixture of (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 g, 36.1 mmol), 2-chloro-3,6-difluorophenol (8.9 g, 54.1 mmol) and PPh3 (9.93 g, 37.8 mmol) in THF (20.5 mL, 252 mmol) was sonicated for several minutes. While sonicating, DIAD (7.5 mL, 37.8 mmol) was slowly added dropwise to the mixture over several minutes and sonicated further for 15 minutes. The mixture was concentrated and then triturated in excess hexanes for 16 hours. The PPh3 oxide precipitate was filtered off and the organic layer was concentrated to yield a yellow oil. The crude mixture was diluted in EtOAc (300 mL), washed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried with anhydrous MgSO4, filtered, and concentrated. The organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes) to yield 14 g of (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a yellow oil which was used in the next step without further purification.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)(=O)=O.[NH3:18].C1COCC1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]([NH2:18])[N:6]=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: N
Reactant: CS(=O)(=O)c1nncc(-c2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: Nc1nncc(-c2ccc(F)cc2)n1
Yield: 74 %

Procedure:
5-(4-Fluorophenyl)-1,2,4-triazin-3-amine (2.80 g, 74%) was prepared from 3-(methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00 g, 19.7 mmol) and 0.5 M ammonia in THF (100 mL, 50.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:26]=[C:25]([S:27]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:38]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:23]2[CH:24]=[C:25]([S:27]([CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:29])=[O:28])[CH:26]=[CH:21][C:22]=2[CH3:38])[CH:11]=1)#[N:16]
Reactant: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-bromo-1-methyl-4-[(2-phenylethyl)sulfonyl]benzene (Intermediate 70), the title compound was obtained as a yellow solid.
Reaction SMILES: I.[CH:2]12[CH2:13][CH2:12][CH:5]([CH2:6][CH:7]1[C:8]([O:10]C)=[O:9])[CH2:4][NH:3]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([S:20]([N:3]2[CH2:4][C@H:5]3[CH2:12][CH2:13][C@@H:2]2[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6]3)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC2CCC1NC2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: I
Product: O=C(O)[C@@H]1C[C@@H]2CC[C@H]1N(S(=O)(=O)c1ccccc1)C2

Procedure:
The title compound was synthesized as in Production Example 1, using methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide and benzenesulfonyl chloride as the raw material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][C:7]=1[NH2:8].[CH2:19](C(CC)(CC)C([O-])([O-])[O-])[CH3:20].[OH-].[NH4+]>C(O)(=O)C>[CH3:19][C:20]1[N:8]=[C:7]2[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]2[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCOC(=O)c1cc(N)c(N)nc1C(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2nc(C)nc-2[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl 5,6-diamino-2,3-pyridinedicarboxylate (10.38 g, 0.041 mol) is stirred under an N2 atmosphere in 100 mL glacial acetic acid, to give a clear orange solution. Triethylorthoacetate (TEOA), (0.19 mol) is then added and the mixture is heated to reflux for 15 hours. The cooled solution is poured into ice water and neutralized with ammonium hydroxide. The solution is extracted with ethyl acetate, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated to an oil. The oil is taken up in ethyl acetate and the desired product is precipitated by the addition of hexanes in two crops of beige solid, totalling 8.11 g (71.3%), having a melting point of 164°-165° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH2:15]([C:17]1[N:21]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[N:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH2:15]([C:17]1[N:21]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[N:20]=[CH:19][C:18]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1)[CH3:16]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cnn1S(=O)(=O)N(C)C
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCc1c(-c2cc3c(s2)C(=O)NC(C)(C)N3C)cnn1S(=O)(=O)N(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 5-ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-sulfonamide (329 mg, 1.00 mmol), cesium carbonate (815 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. for 1 h. The mixture was poured into water (100 mL) and EtOAc (200 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford the title compound (139 mg, 70%) as a yellow solid:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.Cl[C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])=[O:7].[Cl-].[Na+]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])=[O:7]
Reactant: O=C(Cl)N1CCNC1=O
Reactant: CNC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCNC1=O

Procedure:
A mixture of 50 parts by volume of a 50% strength aqueous dimethylamine solution and 70 parts by volume of tetrahydrofurane was adjusted to pH = 8 with 5 N hydrochoric acid. 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were added gradually thereto while stirring and cooling with ice and the pH value was maintained by simultaneous addition of further dimethylamine solution. The mixture was further stirred until the pH was constant, the tetrahydrofurane was then stripped off and the residue was saturated with sodium chloride and repeatedly extracted with ethyl acetate. The organic solution was washed and saturated sodium chloride solution, dried over MgSO4 and filtered, and the solvent was evaporated off. The residue was recrystallized from acetone and dried in a vacuum desiccator over P2O5.
Reaction SMILES: [CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10](Br)[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[SH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[OH-].[K+]>N1C=CC=CC=1>[CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([S:18][C:19]4[S:20][CH:21]=[CH:22][N:23]=4)[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)C1(CC2)OCCO1
Reactant: Sc1nccs1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc2c(cc1Sc1nccs1)C1(CC2)OCCO1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
The bromide from Step 6 (410 mg, 1.37 mmol) and 2-mercaptothiazole (200 mg, 1.7 mmol) were mixed together in pyridine (3 mL) at room temperature. Aqueous KOH (8M, 213 μL, 1.7 mmol) was added and the resulting mixture was heated with an oil bath at 80° C. for 3 h, then at 100° C. for 1.5 h and finally 75° C. for 16 h. After cooling to room temperature the mixture was diluted and EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (from 5% acetone in 2:1 CH2Cl2 -hexanes to 10% acetone in CH2Cl2) yielded 280 mg of the title compound.