Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[C:8]([Mg]Br)#[CH:9].[Cl-].[NH4+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([OH:7])[C:8]#[CH:9])=[CH:2]1
Reactant: O=Cc1ccoc1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-furaldehyde (25.0g, 0.26 mol) in THF (250 mL) at 78° C. was added ethynylmagnesium bromide (572 mL, 0.286, 0.5M THF) at the rate of 10 mL per min. The mixture was slowly warmed to room temperature, stirred for 1 h and then poured into a cooled ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was distilled at 50°-55° C. and 0.24 mm Hg to afford 1-(3-furyl)-1-hydroxy-2-propyne.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)[C:3]=1[S:24]([C:26]([F:29])([F:28])[F:27])=[O:25].CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>C1(C)C=CC=CC=1>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:32][N:33]([CH3:35])[CH3:34])=[C:3]([S:24]([C:26]([F:29])([F:28])[F:27])=[O:25])[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)=[N:5]1
Reactant: COC(OC)N(C)C
Reactant: Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 62.5 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfinylpyraz ole (500 mg, 1.04 mmol) and N,N-dimethylformamide dimethylacetal (90%) (280 mg, 2.12 mmol) were suspended in 20 ml of dry toluene. The resulting suspension was stirred with heating under reflux for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 ml of toluene and then concentrated again under reduced pressure. The resulting concentrated residue was purified by subjecting to silica gel preparative TLC [developing solvent: mixed solvent of hexane and ethyl acetate (volume ratio=3:1)] to obtain 350 mg (0.65 mmol) of the title compound as a colorless crystal. Yield 62.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([NH2:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([NH:9][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11]
Reactant: CCCCOC(=O)N1C[C@H](N)C[C@H]1C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCOC(=O)N1C[C@H](NS(=O)(=O)c2ccc(C)cc2)C[C@H]1C(=O)OC
Yield: 80 %

Procedure:
A 3 ml solution of N-α-butoxycarbonyl-trans-4-amino-L-proline methylester 49 mg (0.20 mmol), triethylamine 0.042 ml (0.30 mmol), p-toluenesulfonyl chloride 42 mg (0.22 mmol) in chloroform was stirred at room temperature for 16 hours. To the reaction solution was added water and the mixture was extracted with chloroform and dried on magnesium sulfate. After filtration and concentration of the mixture, the residue was purified by a column chromatography on silica gel (eluted with a mixed solvent of ethyl acetate and hexane) to give 64 mg (0.16 mmol) of the title compound (yield: 80%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:37]1([CH:42]=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[N:18]([CH2:42][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Reactant: O=CC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CC3CCCC3)c3cc4c(cc32)COC4)n1

Procedure:
To a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.195 mmol) dichloroethane (5 mL), add cyclopentanecarbaldehyde (0.780 mmol) along with a catalytic amount of acetic acid. Add sodium triacetoxyborohydride (0.975 mmol) and stir at room temperature overnight. Quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (5 mL). Dry the organic portion, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (5-35%) to afford the title compound as a colorless foam. MS (ES+): 595.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3](OC1C(C)(C)[C@H]2[C@](C)(CC=1)[C@@H]1[C@](C)([C@@]3(C)[C@H](CC1)[C@H]1[C@H](C(C)=C)CC[C@]1(NCCN1CCS(=O)(=O)CC1)CC3)CC2)(=[O:5])=[O:4].[O:49]=[C:50]1[CH2:55][CH2:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][CH2:51]1.[O:60]=[C:61]1[CH2:66][CH2:65][CH:64]([C:67]([O:69][CH3:70])=[O:68])[CH:63]=[CH:62]1>>[F:1][C:2]([F:48])([F:47])[S:3]([O:49][C:50]1[CH2:55][CH2:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][CH:51]=1)(=[O:5])=[O:4].[O:60]=[C:61]1[CH2:66][CH2:65][C:64]([C:67]([O:69][CH3:70])=[O:68])=[CH:63][CH2:62]1.[O:49]=[C:50]1[CH2:55][CH2:54][CH:53]([C:56]([O:58][CH3:59])=[O:57])[CH:52]=[CH:51]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: COC(=O)C1=CCC(=O)CC1
Agent: COC(=O)C1C=CC(=O)CC1
Product: COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)CC1
Yield: 53.9 %

Procedure:
The title compound was prepared in 53.9% yield following the procedure described in step 6 of method 2 for the preparation of intermediate 1, using methyl 4-oxocyclohex-1-enecarboxylate and methyl 4-oxocyclohex-2-enecarboxylate as the reactants. Methyl 4-oxocyclohex-1-enecarboxylate and methyl 4-oxocyclohex-2-enecarboxylate were prepared following the procedures described in Tet. Lett. Vol. 53, issue 7, page 819-821. m/e 287.05 (M+H)+, 2.435 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.96 (dt, J=6.3, 1.5 Hz, 1H), 6.07 (dt, J=6.4, 1.4 Hz, 1H), 3.78 (s, 3H), 2.81-2.73 (m, 2H), 2.67-2.59 (m, 2H). 19F NMR (376 MHz, CHLOROFORM-d) δ −73.55 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)(=[O:34])=[O:33]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 128.6 %

Procedure:
A mixture of 0.13 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.21 g of 2-chlorobenzenesulfonyl chloride, 0.12 g of triethylamine and 5 mg of N,N-dimethylaminopyridine in 2 ml of methylene chloride is stirred at room temperature for 18 hours. The mixture is partitioned between 1N NaOH and ethyl acetate. The organic layer is washed with 50% NH4Cl and brine, dried over Na2SO4 and evaporated to give 0.26 g of the desired product as a yellow solid. MS(CI):663(M+H; C35).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:4][C:3]([CH3:5])=[CH2:2])=[CH:17][CH:16]=1)[CH3:15]
Reactant: C=C(C)CCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OCC)cc1
Temperature: 90 °C

Procedure:
3-Chloro-2-methylpropene (2.1 mL, 0.021 mol) is added to a stirred N,N-dimethylformamide solution (30 mL) of ethyl 4-hydroxybenzoate (3 g, 0.018 mol). Potassium carbonate (3.2 g, 0.023 mol) is introduced and the mixture is heated at 90° C. for one hour. The reaction mixture is cooled to room temperature and filtered to remove inorganic salts. N,N-dimethylformamide is removed under reduced pressure, Demineralized water (20 mL) is added to the residue and the aqueous layer is extracted with ethyl acetate (3×20 mL). Combined organic layers are washed with demineralized water (2×15 mL) followed by brine and dried over sodium sulphate. Removal of ethyl acetate under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 90:10) to give 4-(2-methylprop-2-enyloxy)benzoic acid ethyl ester.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:14]2[N:18]([CH3:19])[C:17]3[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:24]([OH:26])=O)=[CH:23][C:16]=3[N:15]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]([O:66][C:67](=[O:76])[NH:68][C@@H:69]1[C@H:74]([OH:75])[CH2:73][CH2:72][NH:71][CH2:70]1)([CH3:65])([CH3:64])[CH3:63]>CN(C=O)C.CCOCC.O>[C:62]([O:66][C:67](=[O:76])[NH:68][C@@H:69]1[C@H:74]([OH:75])[CH2:73][CH2:72][N:71]([C:24]([C:22]2[CH:21]=[C:20]([O:27][CH3:28])[C:17]3[N:18]([CH3:19])[C:14]([C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[CH:7]=4)=[N:15][C:16]=3[CH:23]=2)=[O:26])[CH2:70]1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@H]1O
Reactant: COc1cc(C(=O)O)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (105 mg, 0.279 mmol) in DMF (1.5 mL) was added HATU (106 mg, 0.279 mmol) followed by DIPEA (0.097 mL, 0.558 mmol) and the reaction stirred at room temperature for 15 min. tert-Butyl((3S,4R)-4-hydroxypiperidin-3-yl)carbamate (60.3 mg, 0.279 mmol) was added in DMF (1.5 mL) and the reaction stirred at RT for 16 h. LCMS showed complete reaction. Water (20 mL) and Et2O (20 mL) were added and the layers separated. The aqueous layer was extracted with further Et2O (2×20 mL) and the combined organics washed with water (2×20 mL), dried (Na2SO4) and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash chromatography on silica (10 g) using a gradient of DCM→100% (20% MeOH/DCM)/DCM. The appropriate fractions were combined and evaporated under vacuum to give the product as a yellow oil—tert-butyl((3S,4R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-4-hydroxypiperidin-3-yl)carbamate (146 mg, 0.254 mmol, 91% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:10]=2[N:9]=[N:8]1>C1COCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=2[N:9]=[N:8]1
Reactant: COC(=O)c1ccc2[nH]nnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]nnc2c1
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Under a nitrogen atmosphere a dry round-bottom flask was charged with LiAlH4 (0.316 g, 7.90 mmol) and THF (15 mL). Methyl 1H-benzo[d][1,2,3]triazole-5-carboxylate (1.0 g, 5.64 mmol) was then added portion-wise over 10 min at room temperature and reaction allowed to stir for 4 hours at which time the reaction was quenched with EtOAc (5 mL), and the mixture poured into ice-water. The mixture was acidified to pH=3 with 10% H2SO4 and extracted 4× with EtOAc. The combined organics were washed with brine, dried (MgSO4) and the solvent removed. The resulting brown solid was boiled in Et2O and the solids filtered and dried to give the title compound as a light brown solid (678 mg, 81%). 1H NMR (400 MHz, CD3OD) δ 7.85 (m, 2H), 7.47 (d, J=8.4 Hz, 1H), 4.79 (s, 2H); MS ESI 150.0 [M+H]+, calcd for [C7H7N3O+H]+150.16.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([O:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1cnc(C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cc1cnc(C)nc1Oc1cccc(C(F)(F)F)c1

Procedure:
Ethyl α-(2-methyl-4-chloro-5-pyrimidinyl)-acetate (3 g, 14 mmol), 3-trifluoromethyl phenol (3 g, 14 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stirred at +80° C. for 3 hours. The mixture is diluted with ether and washed with brine. Drying over MgSO4 and evaporation of the solvent gives pure ethyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]acetate as an oil.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([CH2:24][O:23][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:15][C@@H:14]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70997.1 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 22; 826 mg, 1.33 mmol), 10% palladium on charcoal (470 mg, 0.44 mmol), ethyl acetate (10 ml) and ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +60° C. for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (500 g, 71%).
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][CH2:6][O:7][C:8]([NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1)=[O:9]>CO>[NH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([N:10]3[CH2:5][CH2:6][O:7][C:8]3=[O:9])[CH:19]=2)[CH:15]=[CH:16]1
Reactant: O=C(Nc1ccc2cc[nH]c2c1)OCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1OCCN1c1ccc2cc[nH]c2c1
Reaction time: 0.25 h

Procedure:
60 ml of methanol are added to 120 ml of a 30% solution of sodium methylate in methanol and 0.25 mol (60 g) of 6-(β-chloroethoxycarbonyl)aminoindole (prepared in accordance with the first step of Example 1) are then added, with stirring. The temperature reaches 50° C. Stirring is continued for 15 minutes after the end of the addition. The precipitate formed is drained, washed with alcohol and then dried. It melts at 199° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+].Cl>CN(C)C=O>[Si:24]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a solution of 4-hydroxymethyl-3-nitrobenzoic acid (1.50 g, 7.62 mmol) and imidazole (1.55 g, 22.8 mmol) in dimethylformamide (20 mL) was added tert-butyldimethyl-silyl chloride (2.23 g, 14.8 mmol), and then the reaction mixture was stirred at room temperature for 15 hours. To the reaction mixture, saturated ammonium chloride aqueous solution was added and acidified with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with saturated ammonium chloride aqueous solution, water and brine, dried with sodium sulfate, filtered, and concentrated under the reduced pressure. The residue was purified by silica gel column chromatography to give the desired product as a white solid (1.73 g, yield 73%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[S:23][CH:27]=[CH:26][N:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1nccs1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4nccs4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 170 mg (1.5 mmol) of thiazole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(thiazol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d)pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)3[(thiazol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=9.8; FAB-MS: (M+H)+=358.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[N:11][N:10]=[N:9]1.Cl[CH:14]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:14]([N:9]2[N:10]=[N:11][CH:12]=[N:8]2)[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: c1nnn[nH]1
Reactant: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(CCc2ccc(F)cc2)n2ncnn2)cc1
Temperature: 25 °C

Procedure:
NaH (0.45 g of 55% suspension in mineral oil) is added to anhydrous DMF under nitrogen atmosphere. Tetrazole (1.1 g) is added and the mixture is gently heated for 20 minutes. The mixture is cooled to room temperature and 1-chloro-1-(4-cyanophenyl)-3-(4-fluorophenyl)propane (1.53 g) is added. The reaction mixture is then heated for 6 hours. Water is added and the products are extracted into ethyl acetate. After drying and solvent evaporation the products are purified by flash chromatography. Elution, starting with pure methylene chloride with increasing methanol content, affords first 2-[1-(4-cyano-phenyl)-3-(4-fluorophenyl)propyl]tetrazole which 1H NMR spectra is as follows:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO>C(Cl)Cl>[Cl:21][CH:15]1[CH:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]([F:20])=[CH:16]1
Reactant: Fc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: FC1=CC(Cl)C(C2CNCCO2)C=C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Dissolve 4-benzyl-2-(2-chloro-4-fluoro-phenyl)morpholine (529 mg, 1.73 mmol) in DCM (2.5 mL). Add 1-chloroethyl chloroformate (1.25 g, 8.65 mmol); heat to 80° C.; and stir overnight. Add MeOH (2.5 mL) and stir at 65° C. for 3 hours. Concentrate under reduced pressure and purify via SCX chromatography eluting with a gradient of 0-100% of (2N NH3/MeOH) in MeOH. Combine the product fractions and remove the solvents under reduced pressure to provide the title compound as a white solid (345 mg, 92%). MS (m/z): 216 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH:23]=[C:24]([C:30]([O:32]CC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:6]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[CH:1]1([N:4]2[C:5]3[C:10](=[CH:9][C:8]([F:11])=[C:7]([N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]4)[N:6]=3)[C:30](=[O:32])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CN(c1ccc(F)c(N2CCN(C(=O)OCC)CC2)n1)C1CC1)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
A solution of 2.3 g (4.8 mmole) of [[cyclopropyl[6-[4-(ethoxycarbonyl)-1-piperazinyl]-5-fluoro-2-pyridinyl]amino]methylene]propanedioic acid, diethyl ester, in 15 ml of acetic anhydride was treated dropwise with 5 ml of 98% sulfuric acid keeping the temperature 55°-60° C. When the addition was complete, the reaction was stirred for one hour and poured onto 50 g of ice. The aqueous suspension was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was triturated with several portions of ethanol/toluene which were also removed in vacuo to give 0.4 g of the title compound, mp 184°-186° C. An additional 0.5 g of product could be obtained by concentrating the original aqueous fraction, mp 184°-186° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:34]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:40]4[CH2:41][CH2:42][N:37]([CH:34]5[CH2:36][CH2:35]5)[CH2:38][CH2:39]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:32])([F:33])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: C1CN(C2CC2)CCN1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(N4CCN(C5CC5)CC4)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and N-cyclopropylpiperazine bis hydrobromic salt (CAS # 159974-58-0). White solid (73%). MS (EI): 610.3 (M+H)+.