Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21]1[O:24][CH:22]1[CH3:23]>>[OH:24][CH:22]([CH3:23])[CH2:21][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3]1
Reactant: CC1CO1
Reactant: CCOC(=O)Cc1ccc(CCN2CCNCC2)cc1
Product: CCOC(=O)Cc1ccc(CCN2CCN(CC(C)O)CC2)cc1
Yield: 92 %

Procedure:
This is prepared analogously to Example 11 by the reaction of ethyl 4-[2-(piperazin-1-yl)-ethyl]-phenylacetate with propylene oxide. Yield 92% of theory; colourless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21])(=[O:4])=[O:3].[ClH:24]>C(Cl)Cl.CCOCC>[ClH:24].[CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[C:20]([F:21])([F:22])[F:23])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CN)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(methylsulfonyl)-3-(trifluoromethyl)benzylcarbamate (420 mg, 1.18 mmol) was dissolved in CH2Cl2 (12 ml) and HCl in Et2O (3 ml, 2M) were added. Resulting mixture was stirred at room temperature overnight followed by evaporation to give 4-(methylsulfonyl)-3-(trifluoromethyl)benzylamine hydrochloride as white solids. This material was used in subsequent reactions without further purification.
Reaction SMILES: CO[C:3]([C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C.N1C=CC=CC=1.S(=O)(=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:3][C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:7][CH:6]=1
Reactant: COC(=O)C1=CCCC(CCOCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)=O
Agent: [Al+3]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=CCCC(CCOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
5-(2-Benzyloxy-ethyl)-cyclohex-1-enecarboxylic acid methyl ester (Intermediate R3 obtained above in Example R1 in accordance with Method R) was reduced with DIBAL. The resulting alcohol (Intermediate R7, 1.18 g, 4.81 mmol) in THF (20 mL) at 0° C. was treated with sulfur trioxide-pyridine. (1.15 g, 7.21 mmol) for 3 h. LiAlH4 (15 mL, 15 mmol) was injected into the mixture at 0° C. The solution was allowed to warm to rt for 18 h. The mixture was subjected to an aqueous work-up and purified by chromatography to give [2-(3-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate R8, 0.90 g, 82%). Deprotection with Na/NH3 and subsequent “Swern” oxidation produced (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9). (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9) was subjected to the applicable steps combined from Method A and Method P to yield 4-(3-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 57).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (1.0 equiv.) in DMF (1.2M) was added EDC (1.0 equiv.) and HOBt (1.0 equiv.) followed by 3-trifluoromethylaniline (1.0 equiv.) and the reaction was stirred at ambient temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was dried with sodium sulfate and concentrated under vacuo. The concentrated crude was purified via silica gel chromatography and eluted with 0 to 100% ethyl acetate in heptanes to give 3-bromo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide in 83% yield. LCMS (m/z) (M+H)=358/360, Rt=1.1 min.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([NH:28][NH:29][C:30](=[O:35])[C:31]([O:33][CH3:34])=[O:32])=O)[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:21][CH2:22][N:23]([C:26]2[O:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[N:29][N:28]=2)[CH2:24][CH2:25]1)=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)C(=O)NNC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: COC(=O)c1nnc(N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Reaction time: 8 h
Yield: 78.2 %

Procedure:
TEA (0.20 ml, 1.34 mmol), para-toluenesulfonyl chloride (255 mg, 1.34 mmol), methyl [2-({4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}carbonyl)hydrazino](oxo)acetate (Intermediate 157) (460 mg, 1.34 mmol) and DCM (8 ml) were combined and stirred overnight. The mixture was diluted with DCM (150 ml) and washed with water (10 ml). The organic phase was separated, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography (DCM/acetone, 8:1 ratio with 1% MeOH) to yield 342 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S(OC1C2C(=CC=C(C(OCC[Si](C)(C)C)=O)C=2)C=NC=1)(=O)=O.C(N(CC)CC)C.[CH3:61][N:62]([CH3:66])[C:63](Cl)=[O:64]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:61][N:62]([CH3:66])[C:63]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH:16]=3)[CH:11]=[N:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:64]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(O)cc3)c2c1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(-c2cncc3ccc(C(=O)OCC[Si](C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Into dichloromethane (6.5 mL), 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)isoquinoline-6-carboxylate (234 mg, 0.64 mmol) synthesized from 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate by the same method as in Example 8 (8a) was dissolved, to which triethylamine (178 μL, 1.28 mmol), 4-dimethylaminopyridine (23 mg, 0.19 mmol) and N,N-dimethylcarbamoyl chloride (88 μL, 0.96 mmol) were added, followed by stirring at room temperature for three hours. The resulting reaction liquid was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (260 mg, yield 93%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[NH:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33]>CN(C=O)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]3[N:19]([CH2:31][C:32](=[O:33])[C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][CH2:16][N:12]3[C:13](=[O:15])[CH:14]=1)[CH2:2]2
Reactant: O=C(CBr)c1ccncc1
Reactant: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(CN1c2nc(N3CC4CCC(C3)O4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccncc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
A solution of 200 mg (0.61 mmol) of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.18 g (3.63 mmol) of cesium carbonate in 10 mL of DMF is heated at 90° C. for 10 minutes. The mixture is cooled to 0° C. and 340 mg (1.21 mmol) of 2-bromo-1-pyrid-4-ylethanone are then added. The reaction is continued for 2 hours at room temperature. The solvent is evaporated off. The residue is purified by chromatography on a column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is recrystallized from acetonitrile to give 16 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:9]1([CH2:15][N:16]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:17]2[C:26]3[N:27]=[C:28]([CH2:30][O:31][CH2:32][CH2:33]OS(C)(=O)=O)[NH:29][C:25]=3[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[C:9]1([CH2:15][N:16]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:17]2[C:26]3[N:27]=[C:28]4[CH2:30][O:31][CH2:32][CH2:33][N:29]4[C:25]=3[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3c2nc2n3CCOC2)cc1
Yield: 87.6 %

Procedure:
Excess potassium carbonate and excess sodium iodide were added to a solution of N,N-bis(phenylmethyl)-2-(2-methylsulfonyloxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.6 g, 1.14 mmole) in acetone (200 mL). The reaction mixture was heated at reflux overnight then concentrated under vacuum. The residue was partitioned between methylene chloride (150 mL) and water (50 mL). The methylene chloride was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with 10:10:80 v/v/v methylene chloride:ethyl acetate:hexanes) to provide 0.42 g of N,N-bis(phenylmethyl)-10,11-dihydro-8H-[1,4]-oxazino[4',3':1,2]imidazo[4,5-c]quinolin-6amine as a white solid.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[CH2:8]([S:15][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: C=C(CBr)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(CSCc1ccccc1)C(=O)O
Reaction time: 23 h
Yield: 89 %

Procedure:
2-Bromomethylacrylic acid (3.00 g, 18.1 mmol) was dissolved in methanol (100 mL), cooled on an ice bath and treated with benzyl mercaptan. Aqueous sodium hydroxide (1N, 39.8 mL) was added dropwise and the reaction mixture was allowed to adjust to room temperature with stirring for 23 hours. Methanol was removed by rotary evaporation at reduced pressure and water (100 mL) was added to the residue, which was then washed with ether. The aqueous layer was cooled on ice and acidified to pH 2.5. The precipitated solid was isolated by filtration and dried to give 2-benzylsulfanylmethyl-acrylic acid (3.346 g, 89%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(=O)C(C)(C)C)cc2n1Cc1ccccc1
Yield: 7.5 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 18 mg, 0.041 mol) in pyridine (1 ml) was reacted with pivaloyl chloride (5.1 μl, 0.41 mmol) to yield the title compound (16 mg, 74%).
Reaction SMILES: [CH:1]1([C:13]([OH:15])=[O:14])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH:2]1[C:10]([OH:12])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH:1]12[C:13](=[O:14])[O:15][C:10](=[O:12])[CH:2]1[CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2
Reactant: O=C(O)C1CCC(C(=O)O)C(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C1CCC2C(=O)OC(=O)C2C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Into a four-necked flask equipped with a thermometer, a stirrer, a condenser and a heat controller, were charged 100 parts of 1,2,4-cyclohexanetricarboxylic acid, 67 parts of acetic anhydride and 333 parts of glacial acetic acid. The contents were stirred for anhydrization at 120° C. for one hour under heating in a nitrogen gas flow. After cooling to 25° C., the precipitated crystals were separated by filtration and dried in a nitrogen gas flow to obtain a white, solid 1,2,4-cyclohexanetricarboxylic acid-1,2-anhydride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([NH:24][CH3:25])=[O:23])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>C(#N)C>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:1][C:2]2[C:3]([C:22]([NH:24][CH3:25])=[O:23])=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@@H:17]4[CH2:21][CH2:20][N:19]([CH2:37][C:36]5[CH:39]=[CH:40][C:33]([Cl:32])=[CH:34][CH:35]=5)[CH2:18]4)=[O:15])[CH:9]=3)=[CH:6][N:7]=2)=[CH:35][CH:34]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)N[C@@H]3CCNC3)c2)cnc1N
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1nc(-c2cccc(C(=O)N[C@@H]3CCN(Cc4ccc(Cl)cc4)C3)c2)cnc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.3 %

Procedure:
To a solution of 3-amino-N-methyl-6-(3-{[(3R)-pyrrolidin-3-ylamino]carbonyl}phenyl)pyrazine-2-carboxamide (34.0 mg, 0.1 mmol) in acetonitrile was added K2CO3 (27.6 mg, 0.2 mmol) followed by 4-chlorobenzyl bromide (30.7 mg, 0.15 mmol). The mixture was allowed to stir at room temperature over 12 h and filtered. The acetonitrile solution was evaporated to dryness, the residue was chromatographed on silica gel using ethyl acetate/hexane 4:1 v/v and trituration of the resulting solid with hexane afforded 3-{[(4-chlorophenyl)methyl]amino}-6-{3-[({(3R)-1-[(4-chlorophenyl) methyl]pyrrolidin-3-yl}amino)carbonyl]phenyl}-N-methylpyrazine-2-carboxamide (28 mg, 47.6%yield): 1H NMR (400 MHz; DMSO-D6): 8.9 (s, 1H); 8.85 (m, 1H); 8.75 (m, 1H); 8.38 (m, 2H); 7.78-7.5 (m, 1H); 4.63 (m, 5H); 3.9 (m, 1H); 3.6 (m, 2H); 3.4 (m, 1H); 2.85 (d, 3H); 2.5 (m, 1H); 2.2 (m, 1H); MS (EI) for C31H30N6O2Cl2: 589 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-].[BH4-].[Na+]>CO.[Pd]>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=1
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2cc(N)cc(C)n2)n1
Yield: 80 %

Procedure:
6,6'-Dimethyl-4-nitro-2,2'-bipyridine-N-oxide (17) (2.0 g, 8.2 mmoles) was dissolved in methanol (20 ml). 10% palladium on carbon (0.36 g) was added followed by slow addition of sodium borohydride (3.6 g, 95 mmoles). After one hour the reaction mixture was filtered and the solution was evaporated. The residue was dissolved in 0.1N sodium hydroxide solution and the product was extracted with chloroform from the water phase. The chloroform phase was dried and evaporated. Yield: 80%
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:31]([CH2:32]OCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21](CC5C=CC=CC=5)[C:22](=[O:23])[C:17]=4[C:16]=3[OH:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(O[C:45]2[CH:46]=[C:47](C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)[CH:48]=[CH:49][C:50]=2OC(F)F)CC1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:31]([CH2:32][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[OH:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(O)c2c(=O)n(Cc3ccccc3)ncc21
Solvent: O
Product: O=c1[nH]ncc2c1c(O)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2Cc1ccccc1
Yield: 42 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 51 mg (0.090 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-hydroxyphenylmethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 20-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with a mixed solvent (chloroform:methanol=9:1 (V/V)). The organic layer after separating the liquids was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 17 mg of the title compound as a white solid. (Yield: 42%)
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:26][C:27]1[C:37]2[N:36](C)[C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1>CCOCC.CCCCCC>[Cl:26][C:27]1[C:37]2[NH:36][C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 3.1 g (0.0082 mol) of 9-chloro-5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (c) of Example 1, 9-chloro-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 121° (ether/n-hexane).
Reaction SMILES: [SH:1][C@@H:2]([CH3:13])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([OH:24])=[O:23].Cl>O>[C:22]([CH:21]([S:1][C@@H:2]([CH3:13])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([OH:24])=[O:23]
Reactant: O=C(O)C(Br)CCc1ccccc1
Reactant: C[C@H](S)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H](SC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(2S)-1-[(2S)-2-Mercaptopropanoyl]-2-pyrrolidinecarboxylic acid (2.0 g), potassium carbonate (2.8 g) and 2-bromo-4-phenylbutanoic acid (2.9 g) were dissolved in water (40 ml), and stirred overnight at room temperature. The reaction mixture was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography to give 2.3 g (62%) of the titled compound: [α]D23 -82.2° (c=1.2, MeOH). IR (KBr, cm-1): 1740, 1720, 1610, 1455, 1438, 1185, 748, 700.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC(F)=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:33]([CH2:36][CH:37]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)[C:39]=2[O:38]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]2[C:39]3[O:38][CH:37]([CH2:36][NH2:33])[CH2:41][C:40]=3[CH:42]=[CH:43][CH:44]=2)=[CH:51][CH:50]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)cc3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(-c3ccc(F)cc3)c2O1
Yield: 64 %

Procedure:
Treatment of (±)-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.1 g, 3.01 mmol) with sodium azide (0.784 g, 12.04 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.074 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.542 g (64%) of (±)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 237-240° C.; Anal. calcd. for C15H14FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 64.26; H, 5.33; N, 4.85.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH:37]([C:39]1[N:40]=[CH:41][NH:42][CH:43]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:37][C:39]4[N:40]=[CH:41][NH:42][CH:43]=4)[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: O=Cc1c[nH]cn1
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]cn4)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo [3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with 4-formylimidazole (0.08 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (20 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.074 g (25%) of pure N2-(4-{4-amino-1-[1-(1H-4-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) 69.446 (s, 1H), 8.252 (s, 1H), 8.126-8.1082 (d, 1H, J=8.16 Hz), 7.7198-7.7 (d, 1H, J=7.92 Hz), 7.6-7.569 (m, 2H), 7.35-7.298 (m, 4H), 7.171-7.134 (m, 1H), 6.946 (s, 1H), 5.422-5.385 (m, 1H), 4.043 (s, 3H), 3.961 (s, 3H), 3.691 (s, 2H), 3.175-3.162 (m, 2H), 2.9-2.883 (m, 3H), 2.385-2.332 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.13 min (100%), MH+ 563.3.