Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[SH:10])=[O:4].C(N(CC)CC)C.Br[CH2:19][CH2:20][C:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([F:23])[F:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[S:10][CH2:19][CH2:20][C:21]([F:23])([F:22])[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:4]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: COC(=O)c1scnc1S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
4-Mercapto-thiazole-5-carboxylic acid methyl ester (0.41 g, 2.16 mmol) is dissolved in DMF (6 ml) and triethylamine (0.45 ml, 3.24 mmol) and 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.55 g, 2.16 mmol) are added successively. The resulting mixture is stirred at RT for 16 h. After completion of the reaction, the mixture is poured onto water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and concentrated to dryness. The crude is purified by column chromatography (silica gel, 20% EtOAc/hexane) yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid methyl ester (0.42 g, 1.2 mmol, 56%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6][CH2:5]2.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][N:4]4[C:10](=[N:1][CH:2]=[CH:3]4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cc(F)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-c1nccn1CCC2
Product: CNC(=O)c1cc(F)ccc1Nc1nc(Nc2ccc3c(c2)-c2nccn2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide was converted to 2-[5-chloro-2-(5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-5-fluoro-N-methyl-benzamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.43 (dd, 1H), 8.19 (s, 1H), 8.12 (d, 1H), 7.76 (d, 1H), 7.69 (dd, 1H), 7.61 (d, 1H), 7.5 (m, 2H), 7.03 (td, 1H), 4.26 (t, 2H), 2.92 (s, 3H), 2.81 (t, 2H), 2.52 (pent, 2H); 19F NMR (282 MHz, CD3OD) δ −77.9, −119.1; MS (m/e) 478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[N:14]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][S:24]2(=[O:31])=[O:30])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:27]2[CH2:26][CH2:25][S:24](=[O:30])(=[O:31])[N:23]([CH2:22][CH2:21][CH2:20][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:29][CH2:28]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S1(=O)CCNCCN1CCCN1CCCCC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CCCN2CCCCC2)S(=O)(=O)CC1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 3,4-dichlorophenyl isocyanate (59 mg, 0.31 mmol) in tetrahydrofuran (0.5 ml) was added dropwise at room temperature to a suspension of 2-(3-piperidin-1-yl-propyl)-[1,2,5]thiadiazepane 1,1-dioxide dihydrochloride (intermediate 13; 100 mg, 0.29 mmol) and triethylamine (116 mg, 1.15 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred for 16 h, then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 95:5:0.25) produced the title compound (117 mg, 88%). White solid, MS (ISP)=463.0 (M+H)+.
Reaction SMILES: [C-]#N.[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>C(#N)C>[O:11]=[C:10]([C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)[CH2:14][CH2:13][C:12]#[N:15]
Reactant: O=Cc1ccncc1
Reactant: C=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: N#CCCC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-1. 4-Oxo-4-(4-pyridinyl)butanenitrile--To a stirred mixture containing 29.4 g. of sodium cyanide and 500 ml. of acetonitrile, after stirring said mixture for ten minutes, was added dropwise over a period of three hours a solution containing 64.2 g. of 4-pyridinecarboxaldehyde in 500 ml. of acetonitrile and the resulting mixture was stirred at room temperature for one hour. To the stirred mixture was added slowly over a period of one hour a solution of 24.5 g. of acrylonitrile in 200 ml. of acetonitrile and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was stripped in vacuo of solvent at a temperature not exceeding 54° C. The semi-solid residue was cooled, mixed well with 400 ml. of chloroform, and the mixture filtered. The chloroform was distilled off in vacuo at a temperature not exceeding 50° C. and the residual oily residue was extracted with three 200 ml. portions of toluene. The toluene solution was filtered through diatomaceous earth and the filtrate was distilled in vacuo below 50° C. to remove the toluene. The residue on chilling crystallized. A tiny sample was saved and the remainder was dissolved in 50 ml. of warm isopropyl alcohol. The solution was cooled and then diluted slowly with 125 ml. of ether, chilled and seeded with a crystal obtained from said tiny sample. The crystalline product that separated was collected, washed with 25 ml. of 1:3 (v:v) mixture of isopropyl alcohol:ether, and air-dried to yield 52.1 g of 4-oxo-4-(4-pyridinyl)butanenitrile, m.p. 53.5°-55° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>COCCOC>[OH:16][CH:15]([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:14][O:13][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[O:2][CH3:1])[C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1OCC1CO1)CCC2=O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCC(O)CN1CCCC1)CCC2=O

Procedure:
A mixture of 6-methoxy-5-oxiranylmethoxy-indan-1-one (Intermediate M, 2.5 g, 0.0106 mole) and pyrrolidine (0.9 mL, 0.011 mole) was stirred in 50 mL of DME at 50° C. for 5 hrs under Argon. Then, 150 mL of ethyl acetate was added and the solution washed with water (2×). Following extraction with 2N HCl, the aqueous acidic layer was made basic with 3N NaOH and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether to yield the title compound. MS m/z 306 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH:7]=1
Reactant: NC1CCOCC1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc(NC2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
4,6-Dichloropyrimidine (3.06 g, 20.5 mmol) was dissolved in dimethylformamide (“DMF”) (20 mL) and Cs2CO3 (10.0 g, 30.8 mmol) was added. Tetrahydro-2H-pyran-4-amine (1.87 g, 18.5 mmol) combined with DMF (5 mL) was added dropwise. A slight exotherm was observed. After agitating at ambient temperature for 2 hours, product peak was seen in LC/MS. Agitation continued overnight. The mixture was then diluted with ethyl acetate (250 mL) and washed 4 times with water, brine, dried and evaporated to give 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.86 g, 13.4 mmol, 65.2% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12].C(OC)(=O)[CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][C:16](=[O:17])[CH:12]=[C:11]([OH:13])[CH2:10]1
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)/C=C/c1ccc(F)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)CC(c2ccc(F)cc2Br)C1

Procedure:
To a 500 mL recovery flask was added (E)-4-(2-bromo-4-fluorophenyl)but-3-en-2-one (1B, 11.9 g, 49.0 mmol, 1.0 eq.) and MeOH (200 mL). Dimethyl malonate (1C, 6.47 g, 49.0 mmol, 1.0 eq.) was added, followed by NaOMe (30% wt in MeOH, 9.6 mL, 51.4 mmol, 1.05 eq.). The reaction mixture was refluxed overnight upon which it was concentrated to a brownish-red solid. The residue was taken up in 1N NaOH (150 mL) and refluxed for 1 h, during which the reaction color proceeded from cloudy-brown, to clear brown, to clear solution with brown precipitate. Concentrated HCl was carefully added until the mixture was acidic by pH paper. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaCl. The aqueous phase was extracted with EtOAc (1×75 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a foamy orange solid that was carried on to the next step without further purification (14.3 g, 100%). ESI-MS: m/z 285.2 (M+H)+.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[O:7].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[C:19]2=[C:29]([OH:35])[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)CC)(C)C>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[C:19]2=[C:29]([O:35][C:10](=[O:11])[CH:9]=[CH:8][C:6]([OH:7])=[O:5])[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)CCOC(=O)C=CC(=O)Cl
Reactant: NC(=O)N1C(=O)C(=C(O)c2cccs2)c2cc(Cl)ccc21
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N1C(=O)C(=C(OC(=O)C=CC(=O)O)c2cccs2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared by the procedure of Example 1 with the exception the 3-(2-trimethylsilylethyloxycarbonyl)propenoyl chloride (1.3 equiv.), 5-chloro-2,3-dihydro-3-[hydroxy-(2-thienyl)methylene]-2-oxo-1H-indole-1-carboxamide and diisopropylethylamine were used. The crude product was purified by flash chromatography (using 98:2 CH2Cl2 /EtOAc as eluant) followed by recrystallization from acetonitrile.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M83) (0.17 g, 0.32 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (98 mg, 74%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[Li][CH2:12]CCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[CH2:12]
Reactant: Cc1ccc(C=O)cc1I
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
This aldehyde (1 mmol)was added to a premixed solution of 1.5 mmol of methyl triphenylphosphonium bromide and 1.2 mmol of n-BuLi in 5 mL of THF at 0° C. and this mixture was stirred for 3-6 h at rt and then processed by extraction and chromatography to give 3-iodo-4-methylstyrene.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][CH2:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([NH2:47])=[N:44][C:43]=1[CH3:48])(=[O:41])=[O:40])([CH3:37])[CH3:36]>>[OH:33][CH2:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([NH:47][C:28]([C:27]2[CH:26]=[N:25][N:18]3[C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:32])([F:31])[F:1])[CH:6]=4)=[N:16][C:17]=23)=[O:29])=[N:44][C:43]=1[CH3:48])(=[O:41])=[O:40])([CH3:37])[CH3:36]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c8) the title compound is obtained as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1CCCBr
Reaction time: 15 h
Yield: 81.3 %

Procedure:
Compound 17-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.58 g) and N-bromosuccinimide (2.40 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.24 g) as a pale-brown oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)C(O)=O)=[O:4].OS(O)(=O)=O.[N-:25]=[N+]=[N-].[Na+]>>[NH2:25][C:11]1[C:10]([Cl:16])=[CH:9][C:8]([F:17])=[C:7]([CH:15]=1)[CH2:6][NH:5][C:3](=[O:4])[C:2]([F:19])([F:18])[F:1]
Reactant: O=C(O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 64668.4 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-57 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid (3.0 g), conc. H2SO4 and sodium azide (0.793 g, 0.012 mmol) to afford 2.1 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:28])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:21]=3)[CH:18]=2)=[C:9]([C:29](O)=[O:30])[CH:8]=[N:7]1>>[N:1]1([C:29]([C:9]2[CH:8]=[N:7][N:6]([CH3:5])[C:10]=2[C:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:21]=3)[CH:18]=2)=[O:28])=[O:30])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1

Procedure:
Using azetidine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (75 mg, 48%). Mp.: 272° C. MS: m/z=403.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[OH:8][C:9]1([CH2:15][CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][CH:18]2[CH2:23][CH2:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(#N)C>[CH3:1][S:2]([NH:5][C:6](=[O:7])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][CH2:23][CH:18]2[N:17]([CH2:16][CH2:15][C:9]3([OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:21](=[O:22])[CH2:20][S:19]2)=[CH:34][CH:33]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N=C=O
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 4 h

Procedure:
A solution of methanesulfonylisocyanate (1.33 g., 0.011 mole) in acetonitrile (10 ml.) is added dropwise during 10 minutes to a solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (3.9 g., 0.01 mole) and triethylamine (1.0 g., 0.01 mole) in acetonitrile (30 ml.). The resulting solution is stored at 25° C. for 4 hours and then evaporated at reduced pressure. The residue is treated with water. The crude product is extracted into chloroform and purified by chromatography on a silica gel column with elution by 4% methanol in chloroform.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH3:14])[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:25](O)[CH3:26]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH3:14])[CH2:9][C:10]([O:12][CH2:25][CH3:26])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(CC(=O)O)c1cccc(O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC(NC)c1cccc(O)c1

Procedure:
3-(3-Hydroxyphenyl)-3-methylaminopropionic acid (24.1 g) obtained from Example 7a was dissolved in ethanol (200 ml), and concentrated sulfuric acid (10 ml) was added dropwise to the solution. The resulting mixture was heated under reflux for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution and the solvent was removed under reduced pressure. The residual aqueous solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound which was used in next step reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[C:11]1([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccc3ccccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccc3ccccc3c2)CCNCC1

Procedure:
Prepare by the method of example 20.10 using 1-tert-butoxycarbonyl-4-(naphth-2-yl)-piperidine-4-carboxylic acid amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24]C)=[O:23])[N:14]([CH3:29])[C:13]=3[CH:30]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([OH:24])=[O:23])[N:14]([CH3:29])[C:13]=3[CH:30]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncccc4Cl)cc3n2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(COc2cccc(C(=O)O)c2)nc2ccc(Oc3ncccc3Cl)cc21
Yield: 66.9 %

Procedure:
Methyl 3-({6-[(3-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (1f) (2.46 g, 5.8 mmol), a 2 M sodium hydroxide aqueous solution (10 mL) and 1,4-dioxane (20 mL) were stirred at 80° C. for two hours. After leaving to cool, the reaction mixture was concentrated and water (100 mL) was added. This aqueous solution was neutralized by adding 1 M hydrochloric acid and the precipitated solid was collected by filtration to obtain the title compound (1.59 g, 67%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([N:39]2[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:31])[CH3:1])[CH:11]=[CH:10][CH:9]=4)[CH2:13][CH2:14]3)=[C:23]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: (M+H)+. 570.3.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11]>C(OCC)C.C(N(CC)CC)C>[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][S:11][C:2]1[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=1
Reactant: CCCCCC(C)(O)CS
Reactant: O=C1CCC2OC12
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCC(C)(O)CSC1=CCCC1=O
Yield: 69.3 %

Procedure:
2,3-Epoxycyclopentanone (1.47 g) and 2.0 g of 2-hydroxy-2-methylheptyl mercaptan were dissolved in 30 ml of diethyl ether, and 30 drops of triethylamine were added. They were reacted at room temperature for 2 hours. The solvent was distilled off from the reaction mixture to afford 4.01 g of a crude product. The crude product was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 2.07 g of 2-(2-hydroxy-2-methylheptylthio)cyclopent-2-en-1-one in a yield of 69%. The product had the following characteristics.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nnnc1CCl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1nnnc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS(m/e): 379.3 (MH+).