Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[O:30][CH2:31][CH2:32][CH2:33]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH:21]=[CH:20][C:19]=1[O:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: FC(F)(F)COc1ccc(OCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
To a 40 ml DMF solution of ethyl 7-hydroxy-chromane-2-carboxylate (1.81 g, 8.15 mmol) and 3-bromopropyl 2-chloro-4-(2,2,2-trifluoroethoxy)phenyl ether (3.4 g, 9.8 mmol) was added cesium carbonate (3.2 g, 9.8 mmol). The resulting suspension was heated to 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on slica gel eluting with 20% AcOEt/hexanes to give the title compound 3.23 g (81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.[I:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[I:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene 25 (3 g, 11.1 mmol), and ρ-iodobenzoyl chloride in 65 mL of methylene chloride was added aluminum trichloride (2.1 g) in three portions and the reaction was stirred 3 hours. It was then poured into ice-water and extracted with methylene chloride. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 3% ethyl acetate-hexanes as eluant the title compound (3.97 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[F:47])=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]>COCCOC.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>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[CH2:39][O:38][C:26]1[CH:25]=[CH:24][C:23]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:37][C:27]=1[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3F)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (112 mg, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (24.81 mg, 0.02 mmol) and sodium carbonate (0.72 ml, 0.72 mmol) were added to a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared by Example 81; 150 mg, 0.36 mmol) in 1,2-dimethoxyethane (3 ml), and the mixture was heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified by MDAP to yield the title compound. 58 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: Cc1cc(Br)ccc1C(C)(C)C#N
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C#N)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred solution of 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 13.0 mmol) in anhydrous THF (75 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (7.16 mL, 14.3 mmol). This reaction mixture is stirred at that temperature 10 min., then N-methoxy-N-methyl-acetamide (2.77 mL, 26.0 mmol) is added and the solution is then warmed up to room temperature over 1 h. Acidic brine (30 mL of brine, 15 mL of 3% HCl aq) is then slowly added and the solution extracted with EtOAc (3×100 mL). The organic layer is dried with MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash-chromatography using a 5 to 20% EtOAc in hexane gradient to provide the expected product 2-(4-acetyl-2-methylphenyl)-2-methylpropanenitrile (1.77 g, 68%) as a yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.84-7.74 (2H, m), 7.43-7.40 (1H, m), 2.70 (3H, s), 2.60 (3H, s), 1.81 (6H, s).
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])C.S(O)(O)(=O)=O.CS[C:24](=N)[NH2:25]>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:16])[NH:25][C:24]1=[N:15]2
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cccc2c1CN1CC(=O)NC1=N2
Yield: 10.7 %

Procedure:
A mixture of N-(2-amino-6-methylbenzyl)glycine ethyl ester (0.972 g, 0.00437 mole) and 2-methyl-2-thiopseudourea sulfate (0.609 g, 0.00219 mole) in absolute ethanol (15 ml) was stirred at reflux for 16 hours. Workup as in Example 2 gave the title compound (47 mg), identical (ir) with authentic material prepared according to the procedure of J. Med. Chem., 18, 224 (1975).
Reaction SMILES: [CH3:1][N:2]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10](=[O:19])[C:4]([C:5]([O:7]CC)=[O:6])=[C:3]1[CH2:20][CH2:21][CH3:22].CO.O>[OH-].[Na+]>[CH3:1][N:2]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10](=[O:19])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(C(=O)OCC)c(=O)cc(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(C(=O)O)c(=O)cc(-c2ccccc2)n1C
Temperature: 85 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
4.5 g (0.015 mol) of ethyl 1-methyl-6-phenyl-2-propyl-4-oxonicotinate is suspended in 60 g of 5% sodium hydroxide in a 1:1 mixture of methanol and water. The mixture is heated at 85° C. and stirred for 21/2 hrs. The solution formed is acidified and the suspension formed is vacuum filtered. The filter cake is dried to afford 2.7 g of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid, mp 150° C. (MDC/ether). An additional 0.5 g of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid is obtained by extraction of the xylene solution with 30 ml of 1% sodium hydroxide and acidification of the basic extract.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][N:3]=1.C[O-].[Na+].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:25]#[N:26])[C:6]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:12][CH:11]=2)=[O:8])=[CH:20][CH:19]=1
Reactant: CSc1ccc(CC#N)cc1
Reactant: CCOC(=O)c1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1ccc(C(C#N)C(=O)c2ccc(C)nc2)cc1

Procedure:
Under an atmosphere of nitrogen, a mixture of 38.5 g (250 mmol) of ethyl 6-methylnicotinate, 29.9 g (500 mmol) of sodium methoxide (90.5%) and 300 ml of toluene was added, at 85-90° C. and over the course of 30 min, to a solution of 47.3 g (250 mmol) of 4-(methylthio)phenylacetonitrile in 75 ml of toluene. This mixture was stirred under reflux for 14 h, then distilled until the overhead temperature exceeded 110° C. and kept at reflux for another 6 h. The reaction mixture was poured into 500 g of ice water, the organic phase was decanted off and the aqueous phase was extracted with 3×100 ml of toluene. The aqueous phase was acidified to pH 6.0 using conc. HCl. The resulting yellow-beige suspension was filtered and the residue was washed with water and dried. This gave 53.9 g (76%) of the title product in the form of a yellow solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:13]([C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:20]([NH:45][CH2:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(CCN)OCC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCC
Yield: 91.7 %

Procedure:
By using an analogous procedure to that described for Reference Example 13, N-(carbobenzyloxy)-L-phenylalanine (2 g, 6.68 mmol), hydroxybenzotriazole (903 mg, 6.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1.28 g, 6.68 mmol), 1-amino-3,3-diethoxypropane (935 mg, 6.36 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.68 mmol) were reacted in anhydrous tetrahydrofuran (32 mL) at room temperature for 16 h, to provide benzyl (1S)-1-benzyl-2-[(3,3-diethoxypropyl)amino]-2-oxoethylcarbamate (2.5 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Br:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][Br:21])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C(Cl)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CBr)n1-2

Procedure:
In the manner given in Preparation 10, 7-chloro-5-phenyl-3H-1,4-benzodiazepine-2-yl hydrazine is reacted with bromoacetyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 8-chloro-1-(bromomethyl)6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 12 8-Fluoro-1-(Chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[CH3:9][NH:10][NH2:11]>C(O)C>[IH:1].[CH3:9][N:10]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:11]
Reactant: CSC1=NCCN1
Reactant: CNN
Agent: I
Solvent: CCO
Product: CN(N)C1=NCCN1
Temperature: -10 °C
Yield: 69 %

Procedure:
A solution of 48.8 g of 2-methylthioimidazoline, hydroiodide, 10.0 g of methylhydrazine and 200 ml of ethanol was refluxed for several hours, then clarified and cooled to -10° C. The solid was collected, washed with ether and dried at 60° C. in vacuo, giving 33.4 g of the desired intermediate, mp 146°-147° C.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][C@@H:37]([OH:40])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CC[C@@H](O)C1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC[C@@H](O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and (R)-1-(4-amino-butyl)-pyrrolidin-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ7.19 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.0, 10 Hz), 5.45 (s, 2H), 4.34 (m, 1H), 3.23 (m, 2H), 2.86 (dd, 1H, J=6.0, 10.4 Hz), 2.78 (m, 1H), 2.65-2.54 (m, 4H), 2.25 (s, 3H), 2.14 (m, 1H), 1.73 (m, 1H), 1.56 (m, 4H) ppm; MS (APCI, m/z): 484 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([O:28][CH2:29][O:30][C:31]([O:33][CH2:34][C:35](O)=[O:36])=[O:32])=[C:16]2[C:21](=[O:22])[N:20]3[C@@H:23]([CH3:26])[CH2:24][O:25][C@@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12].[N:39]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=[CH:40]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:31](=[O:32])([O:33][CH2:34][C:35]([NH:47][CH2:46][CH2:45][CH2:44][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1)=[O:36])[O:30][CH2:29][O:28][C:15]1[C:14](=[O:38])[C:13]([C:11]([NH:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:12])=[CH:27][N:17]2[C:16]=1[C:21](=[O:22])[N:20]1[C@@H:23]([CH3:26])[CH2:24][O:25][C@@H:19]1[CH2:18]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)O)c3C(=O)N12
Reactant: NCCCn1ccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)NCCCn4ccnc4)c3C(=O)N12

Procedure:
The title compound was prepared from ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetic acid (63 mg, 0.112 mmol), [3-(1H-imidazol-1-yl)propyl]amine (0.02 mL, 0.176 mmol), N,N-diisopropylethylamine (0.03 mL, 0.176 mmol), and HATU (67 mg, 0.176 mmol), using a process similar to that described in example 16, step (a). Purification by silica gel chromatography yielded the title compound as a white solid. 1H NMR (CDCl3) δ 10.04 (m, 1H), 8.16 (s, 1H), 7.54 (m, 1H), 7.47 (s, 1H), 7.30 (m, 1H), 6.94 (s, 1H), 6.87 (s, 1H), 6.77 (m, 2H), 6.00 (d, J=6.8 Hz, 1H), 5.65 (d, J=6.8 Hz, 1H), 5.31-5.25 (m, 2H), 4.62-4.41 (m, 4H), 4.31 (m, 1H), 4.19 (m, 1H), 4.01-3.29 (m, 3H), 3.02 (m, 1H), 3.36 (m, 1H), 3.03 (m, 1H), 1.97 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). ES+ MS:645 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:27](Cl)(=[O:35])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:28]([C:27]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N(C(=O)Oc2ccccc2)c2ccccc2/C=C/c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.00 g of (E)-4-[2-{2-[N-(4-methoxybenzenesulfonyl)amino]phenyl}ethenyl]pyridine was suspended in 40 ml of chloroform and, after adding 1.82 g of phenyl chlorocarbonate, 1.20 g of triethylamine was slowly added under ice cooling. Then, the mixture was stirred at room temperature for 5 minutes. The solvent was distilled off under reduced pressure and the desired product was purified by silica gel column (carrier: Wako Gel C200, developing solvent chloroform) to obtain the desired compound. The desired compound was treated with ethanol to obtain 0.71 g of a white granular crystal.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:12]([C:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH:23]=3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:12]([C@@H:22]3[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2c(n1)c(C1=CCC(O)CC1)cn2-c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCNc1ncc2c(n1)c([C@H]1CC[C@@H](O)CC1)cn2-c1ccc(F)cc1
Reaction time: 3 h

Procedure:
A mixture of 4-(2-(butylamino)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohex-3-enol (0.095 g, 0.25 mmol) and Pd/C (0.01 g, 10 wt %) in 5 mL MeOH was stirred under H2 atmosphere for 3 h. After filter through a plug of celite, the filtrate was concentrated and purified by Prep-HPLC. The cis-4-(2-(butylamino)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol was obtained as the major product (0.040 g). The trans-4-(2-(butylamino)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol was co-elute with 4-(2-(butylamino)-5-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohexanol (0.035 g).
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:17][CH3:18])[CH2:8][CH2:9][NH:10][C:11](=O)[C:12](F)(F)F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)C=C.[OH-].[K+]>CC(C)=O>[C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:17][CH3:18])[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=[CH2:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(CCNC(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCNCCC(OC)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 93 %

Procedure:
16.7 g. of N-(3,3-diphenyl-3-methoxypropyl)-trifluoroacetamide, prepared according to Example 4, and 24.2 g. of allyl bromide in 150 ml. of anhydrous acetone are heated to 50°C. and 11.2 g. of powdered potassium hydroxide are added. The mixture is then boiled for 5 minutes and the solvent is distilled off in vacuo. The residue is boiled for one hour with 100 ml. of water and 100 ml. of methanol and is worked up as in Example 4. 13.1 g. of 1,1-diphenyl-1-methoxy-3-allylaminopropane of melting point 45° to 50°C. are obtained, corresponding to a yield of 93% of theory.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)=[O:6])[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1c[nH]c2ccccc12
Product: O=C(NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1)c1ccccc1
Temperature: 160 °C
Yield: 39.8 %

Procedure:
A mixture of 3-(4-chlorobutyryl)indole (22.2g. 0.1 mol.) and 4-benzamidopiperidine (40.8g. 0.2 mol.) was stirred and heated at 160° C. for 1 hour. The melt was cooled and extracted under reflux with water (200 ml.) for 0.5 hour. The insoluble granular residue was collected by filtration and crystallised from a mixture of ethanol (150 ml) and water (50 ml.), with charcoal treatment, to yield the title compound (15.5 g. 40%). The hydrochloride was precipitated from a solution of the base, in ethanol by addition of ethanolic hydrogen chloride (16.2 g. 38%) m.p. 275°-6° C. C24H27N3O. HCl 1/4 H2O requires C, 67.0 H, 6.7; N, 9.8 Found: C, 67.0; H, 6.7; N, 9.7%. It can also be precipitated from a solution of the base in dimethylformamide by addition of ethanolic hydrogen chloride and propan-2-ol. This gives the anhydrous form of the title compound hydrochloride m.p. 285.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N+:9]([O-:35])=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reaction time: 2.5 h

Procedure:
A mixture of 4.2 g (11 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester and 3.15 g (14.5 mmol) of m-chloroperbenzoic acid in 100 ml of methlene chloride was stirred at 0° for 2.5 hr. The mixture was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 224°-226°. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, mp 226°-227°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH:3]=[N:2]1.[ClH:19]>O1CCOCC1>[ClH:19].[NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cn[nH]c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1n[nH]cc1C1CCCNC1
Yield: 47 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of tert-butyl 3-(1H-pyrazol-4-yl)piperidine-1-carboxylate (3.6 g, 14.34 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) and hydrogen chloride (6M, 20 mL). The resulting solution was heated to reflux for 1 hour. Upon completion, the resulting mixture was cooled down and concentrated on a rotary evaporator affording 3-(1H-pyrazol-4-yl)piperidine hydrochloride as white solid (1.5 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[C@@H:17]([CH3:27])[CH2:18][NH:19]C(=O)OC(C)(C)C>>[NH2:19][CH2:18][C@H:17]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:27]
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Product: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 3(g) starting from 2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (14.9 mmol, 3.3 g) and (S)-tert-butyl (2-hydroxypropyl)carbamate (29.8 mmol, 5.23 g). Yield 2.2 g. 1H-NMR (400 MHz; CDCl3): δ 1.53 (d, 3H), 3.44-3.61 (m, 2H), 4.48-4.54 (m, 1H), 6.59 (d, 1H), 7.48 (d, 1H), 7.55 (d, 1H), 7.75 (s, 1H). LC-MS: [M+1]=279.12.