Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:3]=1[F:19].O.[NH2:21][NH2:22]>CS(C)=O>[F:19][C:3]1[C:4]([N:9]([CH3:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:5][C:6]([CH3:8])=[N:7][C:2]=1[NH:21][NH2:22]
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N(C)CCc2ccncc2)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N(C)CCc2ccncc2)n1
Reaction time: 8 h
Yield: 63 %

Procedure:
6-Chloro-5-fluoro-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (350 mg, 1.25 mmol) was dissolved in 4 ml of DMSO and 4 ml of hydrazine monohydrate was added. The mixture was stirred overnight and was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (220 mg, 63%). LCMS: (M+H)+: 277.2.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:18][C:19]=1[CH3:20].O>CN(C)C=O>[CH3:20][C:19]1[S:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: COC(=O)c1cc(O)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2nc(-c3ccccc3)sc2C)no1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.51 g) in N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.07 g) at 0° C. After stirring for 30 min., 4-chloromethyl-5-methyl-2-phenylthiazole (5.00 g) was added. After stirring at 60° C. for 2 hrs, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolecarboxylate (5.42 g, 74%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N([CH2:20][CH3:21])CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C@@H:20]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Temperature: 0 °C
Yield: 41275.6 %

Procedure:
To ethanol (55 ml) cooled to 0° C. was added acetyl bromide (41 ml, 0.6 mol) dropwise, followed by a solution of (S)-4-methyl-dihydro-furan-2-one (Tetrahedron 1983, 39, 3107; 18.6 g, 0.2 mol) in ethanol (20 ml). The ice bath was removed and the reaction allowed to reach room temperature. After 2 h of stirring the reaction was concentrated, the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated affording (S)-4-bromo-3-methyl-butyric acid ethyl ester (33.6 g, quant). This was redissolved in ethanol (100 ml), cooled to 0° C. and N-benzylglycine ethyl ester (28.2 g, 0.14 mol) and triethylamine (22.4 ml, 0.16 mmol) were added. The reaction was then warmed to 75° C. for 4 d after which time the reaction was concentrated, the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 5:95) afforded the titled product as a light gold oil (20.3 g, 43%). MS (ISP)=322.2 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:40])[CH2:31][N:32]3[CH:36]=[CH:35][C:34]([CH:37]4[CH2:39][CH2:38]4)=[N:33]3)[CH:26]=[N:27][CH:28]=2)=[O:22])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1>[CH:37]1([C:34]2[CH:35]=[CH:36][N:32]([CH2:31][C:30]([NH:29][C:25]3[CH:26]=[N:27][CH:28]=[C:23]([C:21]([C:13]4[C:14]5[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=5[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][OH:6])[CH:12]=4)=[O:22])[CH:24]=3)=[O:40])[N:33]=2)[CH2:38][CH2:39]1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3ccc(C4CC4)n3)c2)c2cncc(F)c21
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3ccc(C4CC4)n3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(3-cyclopropyl-pyrazol-1-yl)-acetamide (Preparation 6, 40 mg, 67 μmol) in THF (5 mL) 4M dioxane-HCl (1 mL) was added and stirred at room temperature for 18 hours. The reaction was evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid in 92% yield, 30 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCN(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
To a stirred solution of 1-(3-chloropyridin-2-yl)piperazine (316 mg, 1.6 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.975 mL, 5.6 mmol) then 4-tert-butylbenzene-1-sulfonyl chloride (372.4 mg, 1.6 mmol). The mixture was stirred at room temperature for 1.5 hour. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)piperazine in 59.3% yield (374 mg) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[S:24])[NH2:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Product: NC(=S)CCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
A mixture of 3-(4-nitrophenyl)propanamide (0.50 g), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.81 g) and pyridine (5 mL) was stirred at 50° C. for 15 hrs. The reaction mixture was concentrated, and 1N hydrochloric acid was added to the obtained residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-(4-nitrophenyl)propanethioamide as colorless crystals (0.40 g, yield 73%) from a fraction eluted with hexane-ethyl acetate (2:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess (trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([NH2:14])=O)[C:8]=2O)[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]#[N:14])[C:8]=2[Cl:17])[CH:3]=1
Reactant: NC(=O)c1cnc2cc(Br)sc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2cc(Br)sc2c1Cl

Procedure:
A mixture of ethyl 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (1.3 g, 4.3 mmol) [Elliott, R.; O'Hanlon, P. J.; Rodgers, N. B. Tetrahedron, 43(14), 3295 (1987)] in 20 mL of ethanol and 6 mL of 2.5 N sodium hydroxide is heated at reflux for 4 hours. The mixture is poured into ice water and the pH is adjusted to 5-6 by the addition of acetic acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 840 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylic acid. A mixture of 2-bromo-7-hydroxythieno[2,3-b]pyridine-6-carboxylic acid (810 mg, 2.95 mmol) and N,N-carbonyldiimidazole (1.0 g, 6.17 mmol) in 15 mL of N,N′-dimethylformamide is heated at 65° C. for 2 hours. The mixture is poured into 50 mL of ice cold aqueous ammonium hydroxide and stirred for 14 hours. The resultant solids are collected by filtration washing with water to provide 800 mg of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide. A mixture of 2-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (273 mg, 1.0 mmol) and 3 mL of phosphorous oxychloride is heated at reflux for 1 hour. The solvent is removed in vacuo and the residue is poured into ice water and treated with sodium bicarbonate. The resultant solids are collected by filtration washing with water. The solids are purified by flash column chromatography eluting with chloroform to provide 240 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 198-199° C.; 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 9.11 (s, 1H); MS 273.1, 275.1, 277.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=[O:20])[CH3:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH3:30][N:31]([CH3:33])/[CH:32]=[CH:19]/[C:18]([C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:3][N:4]([CH3:8])[CH3:5])[C:3]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:20]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2c(N)cccn12
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C=Nc1cccn2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 1-[8-amino-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]ethanone (150 mg, 0.56 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL) was heated at reflux for 6 days. The mixture was cooled to room temperature, ethyl acetate and water were added. The phases were separated and the organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by silica gel chromatography (1:1 acetone:ethyl acetate) gave 130 mg (62%) of N′-[3-[(2E)-3-(dimethylamino)-2-propenoyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide as a foam. 1H NMR (CDCl3): δ 9.28 (d, 1H), 8.53 (s, 1H), 7.76 (q, 2H), 7.62 (d, 1H), 7.13 (t, 2H), 6.87 (m, 2H), 5.12 (d, 1H), 2.4–3.3 (m, 12H); MS m/z 380 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:8]([I:9])=[C:7]([C:10]([O:12][CH2:13]C)=[O:11])[N:6]([CH3:15])[N:5]=2)[CH2:3][CH2:2]1.CN1C(C(OC)=O)=CC(C2C=C[C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=N1.II>>[I:9][C:8]1[C:4]([C:1]2[CH:3]=[CH:2][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:5][N:6]([CH3:15])[C:7]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Reactant: CCOC(=O)c1c(I)c(C2CC2)nn1C
Agent: II
Product: COC(=O)c1c(I)c(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
This compound is prepared analogously to the preparation of ethyl 3-cyclopropyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate from methyl 1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate and iodine.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1.[F:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[CH:19][N:18]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[C:22]([C:2]2[C:6]([C:7]3[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][S:4][CH:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: CCNc1ncccc1-c1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCNc1ncccc1-c1cscc1-c1cccnc1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 23.5 %

Procedure:
A mixture of 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene (0.31 g), 2-fluoro-3-tributylstannylpyridine (0.507 g) and Pd(Ph3P)2Cl2 (0.035 g) in N-methylpyrrolidinone (3 mL), in a sealed tube, was heated at 100° C. for 17 hours. The mixture was cooled and tetrabutylammonium fluoride (1M in tetrahydrofuran, 1 mL) was added. After one day, the mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated. The residue was fractionated by chromatography to give 3-(2-fluoropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.077 g) mp 127-129° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[CH2:14]([S:17](Cl)(=[O:19])=[O:18])[CH2:15][CH3:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:17]([CH2:14][CH2:15][CH3:16])(=[O:19])=[O:18])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
According to the general procedure described in Example 1-C, 3-methyl-4-aminophenyl N-methylcarbamate (4.0g., 0.022 mole) was reacted with n-propanesulfonyl chloride (31.5g., 0.022 mole) and triethylamine (2.47g., 0.024 mole) in benzene. The product (4.0g.) showed the characteristic carbonyl absorption at 5.8μ in the infrared (KBr).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:43])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH2:34][OH:35])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:45][C:2]([F:1])([F:44])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:43])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH2:34][OH:35])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:17])([F:18])[F:19])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H](CCC(F)(F)F)[C@@H](CCC(F)(F)F)C(=O)NC1N=C(c2cccc(F)c2)c2cccc(CO)c2NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2c(CO)cccc2C(c2cccc(F)c2)=NC1NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a solution of Intermediate 37I (65 mg, 0.100 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 3 h and then concentrated to dryness. The crude material was purified by preparative reversed-phase HPLC (aq. MeOH, containing 0.1% TFA). The desired fractions were combined and concentrated to dryness to afford Intermediate 37J (30 mg, 51%). HPLC: RT=2.680 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=592.3 [M+H+].
Reaction SMILES: [CH:1]1([N:4]([C:12]2[C:17]([CH3:18])=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=3[F:30])[N:15]=[CH:14][N:13]=2)[CH2:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>C1COCC1>[CH:42]([O:41][C:39]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:12]2[C:17]([CH3:18])=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][C:21]=3[F:30])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:8]1)=[O:40])([CH3:44])[CH3:43]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1N(CC1CCNCC1)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1N(CC1CCN(C(=O)OC(C)C)CC1)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A mixture of cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-piperidin-4-ylmethyl-amine (65 mg, 0.15 mmole) and triethylamine (23 mg, 0.225 mmole) in 2 mL THF was stirred at room temperature for 10 minutes. Into this mixture was added drop-wise isopropyl chloroformate (0.225 mmole). The mixture was quenched with water, extracted with ethyl acetate, and dried in vacuum to give Compound D2 as a yellow solid (65 mg, 83%). 1H NMR (CDCl3, 400 MHz) δ 0.69-0.64 (m, 2H), 0.83-0.88 (m, 2H), 1.12-1.15 (m, 2H), 1.23 (d, J=6.3 Hz, 6H), 1.72 (d, J=13.1 Hz, 2H), 1.94-2.02 (m, 1H), 2.04 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.97-3.17 (m, 1H), 3.10 (s, 3H), 3.49-3.55 (m, 2H), 4.09-4.23 (m, 2H), 4.90 (sept, J=6.3 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 7.76-7.80 (m, 2H), 8.12 (s, 1H). Exact mass calculated for C25H33FN4O5S 520.2, found 521.5 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=O)[CH:18]=2)[CH:13]=[N:12]1>CO.N1CCCCC1>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:5]4[C:4]/3=[CH:9][CH:8]=[CH:7][N:6]=4)[CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ncccc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To a mixture of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and 1H-indazole-6-carbaldehyde (29.2 mg, 0.2 mmol) in MeOH (2 mL) was added 1 drop of piperidine via syringe needle. The resulting mixture was refluxed for 2 h (oil temp. 70° C.) and then cooled to rt. The resulting precipitate was collected by suction filtration to give the title compound as a yellow solid (37 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H, NH), 11.25 (s, 1H, NH), 8.16 (s, 1H), 8.10 (d, J=5.2 Hz, 1H), 7.93-7.87 (m, 4H), 7.44 (d, J=8.8 Hz, 1H), 6.90 (dd, J=7.6 Hz, 5.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[N:3]=[C:2]2[NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Cc1nc(Cl)c2ccc(C)c(I)c2n1
Solvent: CC(C)O
Product: Cc1nc(Nc2cccc(OC(F)(F)F)c2)c2ccc(C)c(I)c2n1
Temperature: 170 °C
Yield: 74.1 %

Procedure:
4-Chloro-8-iodo-2,7-dimethylquinazoline (0.30 g, 0.94 mmol) and 3-(trifluoromethoxy)benzenamine (0.20 g, 1.1 mmol) were placed in a microwave vial containing 3 mL of IPA. The vial was capped and heated in a microwave reactor at 170° C. for 10 min. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was dried with sodium sulfate, concentrated and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give a 8-iodo-2,7-dimethyl-N-(3-(trifluoromethoxy)phenyl)quinazolin-4-amine (0.32 g, 74%) as an off-white solid. MS (M+H)+ 460.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:31])=[O:32])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (300 mg, 0.51 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-ethyl)phenyl boronic acid to provide 3-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19](OC(C)=O)=[O:20].S(=O)(=O)(O)O>C(O)C>[C:19]([NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[N:4][C:3]=1[C:15]([NH2:17])=[O:16])(=[O:20])[CH3:18]
Reactant: NC(=O)c1nnn(Cc2ccccc2Cl)c1N
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC(=O)Nc1c(C(N)=O)nnn1Cc1ccccc1Cl
Reaction time: 0.5 h

Procedure:
10,1 g of 5-amino-1-(o-chlorobenzyl)-1H-triazole-4-carboxamide are added, portionwise with stirring, to a mixture of 30,7 g of acetanhydride and 0,1 ml of sulphuric acid and heated to 60° . Stirring is continued for additional 30 minutes at 60° to 70° , the reaction mixture is poored into 250 ml of ethanol, heated to reflux for 30 minutes and evaporated in vacuo to dryness. The residue is triturated with 250 ml of ethyl acetate, the crystalline precipitate is collected and re-crystallised from ethyl acetate yielding 5-acetylamino-1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide of m.p. 181°-183°.