Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][CH:32]([OH:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][C:32](=[O:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC(O)CO[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Dess-Martin periodinane (5.0 g, 11.8 mmol) in anhydrous dichloromethane (35 mL) at room temperature was added a solution of [4-(tert-butyldimethylsilanyloxy)-3-hydroxybutyl]carbamic acid tert-butyl ester (3.77 g, 11.8 mmol) in anhydrous dichloromethane. The resulting mixture was stirred at room temperature for one hour, evaporated in vacuo to one third of the initial volume and applied to a column packed with silica. Elution with ethyl acetate—petroleum ether solvent mixture afforded a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH3:19])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].Cl>C(OCC)C>[CH2:1]([N:3]([CH3:19])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CCN(C)C(=O)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 158.7 %

Procedure:
To a solution of (R)-tert-butyl 3-(ethyl(methyl)carbamoyl)piperidine-1-carboxylate (1 g, 3.7 mmol) in diethyl ether (10 mL) at 0° C. was added ethereal hydrogen chloride (15 mL). The reaction mixture was warmed to room temperature and was stirred at that temperature for 30 min. The solvent was distilled and the resulting residue was washed with diethyl ether to afford (R)—N-ethyl-N-methylpiperidine-3-carboxamide (1 g). MS (ES+) (M+H) 171.23; LCMS retention time 2.38 min (Method M1).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:22][NH:23][CH2:24][C:25](=[O:43])[CH:26]([NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:35]([NH:34][CH:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:25](=[O:43])[CH2:24][N:23]([CH2:2][C:3]([N:5]1[C@H:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4])[CH3:22])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)C1Cc2ccccc2CN1C(=O)CBr
Reactant: CNCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)CC(=O)N1Cc2ccccc2C[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-(bromoacetyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1,1-dimethylethyl ester (2.12 g., 6 mmole) in dimethylformamide (20 ml.) is added (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide (2.0 g., 6 mmole), prepared as set forth in Example 91(b), and diisopropylethylamine (0.77 g., 1.04 ml., 6 mmole). The reaction mixture is stirred overnight, poured into water (50 ml.) and extracted with ethyl acetate (3×50 ml.). The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (twice) and water (twice), dried (Na2SO4), and concentrated into a yellow oily residue (2.9 g.). Flash chromatography (200 g. Merck silica, 2% methanol/chloroform) gives 0.68 g. (S)-2-[[[3-(benzoylamino)-2-oxo-4-phenylbutyl]methylamino]acetyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1,1-dimethylethyl ester as a yellow dried up foam.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:25][C:26]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:19]([C:15]1[CH:14]=[C:13]([NH:12][C:8]2[C:9]3[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([NH:25][C:26]4[C:31]([C:32]5[CH:37]=[CH:36][N:35]=[CH:34][N:33]=5)=[CH:30][CH:29]=[CH:28][N:27]=4)[C:4]=3[CH:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: Cc1ccc2c(Nc3cccc(C#C[Si](C)(C)C)c3)nccc2c1Nc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cccc(Nc2nccc3c(Nc4ncccc4-c4ccncn4)c(C)ccc23)c1
Temperature: 70 °C

Procedure:
Suspended 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)-N1-(3-(2-(trimethylsilyl)ethynyl)phenyl)isoquinoline-1,5-diamine (0.110 g, 0.220 mmol) in methanol (2.5 mL) and added potassium carbonate (0.0607 g, 0.439 mmol). Heated to 70° C. in a sealed tube for 90 minutes. The crude mixture was diluted with water and extracted with two portions of EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The resulting yellow solid was recrystallized from MeOH/Et2O and filtered to afford N1-(3-ethynylphenyl)-6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine. MS (M+H)+ 429.
Reaction SMILES: [F:1][CH:2]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18])[CH:3]=O.[NH2:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:1][CH:2]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18])[CH2:3][NH:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC(F)C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CC(F)CNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Reaction time: 14 h
Yield: 17.5 %

Procedure:
A crude product of 2-Fluoro-3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (196 mg) and 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 147 mg, 0.595 mmol) were dissolved in a mixed solution of dichloromethane (20 ml) and N,N-dimethylformamide (2 ml). Acetic acid (0.068 ml, 1.190 mmol) and anhydrous sodium sulfate (300 mg) were added to the solution at room temperature and the mixture was stirred for 14 hours. Sodium triacetoxyborohydride (252 mg, 1.190 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue and the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and preparative thin layer chromatography (silica gel, chloroform/methanol=20:1) to yield 50 mg (18%) of the title compound in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.BrCC[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][C:28]1C=CC(F)=C[C:29]=1CCBr>>[F:26][C:24]1[CH:25]=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:22][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(Oc2ccc(F)cc2CCBr)c(CCBr)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(F)cc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-bromoethyl-4-fluorophenylether: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 6.92 (t, J=8.6 Hz, 2H), 6.69 (m, 2H), 6.59 (s, 1H), 4.53 (t, J=5.3 Hz, 2H), 4.20 (t, J=5.3 Hz, 2H), 2.57 (s, 3H): MS (ES) m/z 363 (M+1).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4ccc(Cl)cc4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 4-chlorophenyl boronic acid according to the procedure of Example 2, m.p. 131-133.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]3[C:20]([C:19]4=[C:21]5[C:11]3=[CH:12][CH:13]=[CH:14][C:15]5=[CH:16][CH:17]=[CH:18]4)=[C:6]2[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:39]([O:46]CC)([O:43]CC)OCC.Cl>C1COCC1.CCCCCC>[C:22]1([C:9]2[CH:8]=[C:7]3[C:2]([B:39]([OH:43])[OH:46])=[CH:3][CH:4]=[C:5]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:6]3=[C:20]3[C:10]=2[C:11]2[C:21]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]3=4)[CH:14]=[CH:13][CH:12]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc(-c2ccccc2)c2c3c(c(-c4ccccc4)cc12)-c1cccc2cccc-3c12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccccc2)c2c3c(c(-c4ccccc4)cc12)-c1cccc2cccc-3c12
Temperature: -80 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
An amount of 3 g (6.21 mmol) of 9-bromo-7,12-diphenylbenzofluoranthene synthesized in the same manner as in Exemplary Synthesis 1 was dissolved in dehydrated THF and cooled to −80° C. Then, 4.3 ml (6.8 mmol) of a solution of n butyllithium in n-hexane was added dropwise. Forty minutes later, 1.81 g (12.4 mmol) of triethyl borate was added. After two-hour reaction, a diluted hydrochloric acid solution was passed and allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 1.51 g (3.37 mmol) of 7,12-diphenylbenzofluoranthene-9-boronic acid. The yield was 54.3%.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[S:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[S:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Yield: 77.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (146 mg, 0.236 mmol) prepared in Example 9b, triethylsilane (0.3 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (86.0 mg, 78%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)=[O:17]>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([CH:16]=[O:17])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Yield: 67.3 %

Procedure:
In the same manner as that described in Example 2(1) a reaction was carried out using commercially available 4-chloroaniline (354 mg, 2.8 mmol), triethylamine (0.7 ml, 5.0 mmol), 4-formylbenzoyl chloride (700 mg, 4.2 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford 4′-chloro-4-formylbenzanilide (489 mg, yield 68%) as a white solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](NS(C)(=O)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol), in anhydrous CH2Cl2 (5 mL) under argon were added methane sulfonyl chloride (0.23 mL, 2.99 mmol) and Pyridine (0.30 mL, 3.73 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1 N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.NC(N)=[S:13]>C(O)C>[NH:10]1[C:3]2[C:2](=[S:13])[NH:7][CH:6]=[N:5][C:4]=2[P:8]=[CH:9]1
Reactant: Clc1ncnc2pc[nH]c12
Reactant: NC(N)=S
Solvent: CCO
Product: S=c1[nH]cnc2pc[nH]c12
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of 7-chloro-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 14, 0.23 g, 1.33 mmol), thiourea (0.15 g, 2.0 mmol) and absolute ethanol (10 mL) was heated under reflux for 90 min with stirring under anhydrous conditions. The reaction mixture was cooled to 25° C. and then the solvent was evaporated in vacuo. The residue was sonicated with ice-cold water (10 mL) and the precipitate was collected by filtration, washed with cold water (3×5 mL) and dried over P2O5 in vacuo first at 25° C. and then at 100° C. to yield 0.12 g (55%) of the title compound, mp>300° C. Ir (KBr): ν710 (=P-C), 1170 and 1200 (-P=CH), 1580 (C=S), and 3280 (NH) cm-1. Uv (MeOH): λmax230 nm (ε19,400), 276 (9400), and 338 (17,200). 1H nmr (DMSO-d6): 8.11 (s, 1 H, C5H), 8.93 (dd, 1 H, JC2H,NH =5.4 Hz, JC2H,P =39.6 Hz, C2H), δ 13.15 (s, 1 H, NH), and 13.82 (s, 1 H, NH). Anal. Calcd. for C5H4N3PS.H2O: C, 32.08; H, 3.23; N, 22.45; S, 17.13. Found: C, 32.39; H, 3.61; N, 22.54; S, 17.40. ##STR11##
Reaction SMILES: [H][H].Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]>[Pd]>[ClH:4].[Cl:4][C:5]1[CH:6]=[C:7]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Clc1ccc(C2=CCNCC2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: Clc1ccc(C2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 144.6 %

Procedure:
A balloon filled with hydrogen was charged into a solution of 4-(3,4-dichlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (107 mg, 0.41 mmol) in the presence of 5% Pd/C (5% mmol) after the system was degassed. The reaction was stirred at rt for 2 h, filtered, rinsed with MeOH and then concentrated to give 4-(3,4-Dichlorophenyl)piperidine hydrochloride (79 mg, 72% yield) as an oil. MS found: 266.4 (M+).
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([S:22][C:23]#[N:24])[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:25]([C:19]1[C:20]([S:22][C:23]#[N:24])=[N:21][C:16]([N:15]2[C:8]3[CH:9]=[C:10]([C:11]#[N:12])[CH:13]=[CH:14][C:7]=3[N:6]=[CH:5]2)=[N:17][CH:18]=1)([O-:27])=[O:26]
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CSc1nc(-n2cnc3ccc(C#N)cc32)ncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To the solution of 0.58 g (1.25 mmol) 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile in 10 mL 30% (v/v) TFA in DCM was added 0.01 mL of triethylsilane. The mixture was stirred for 0.5 hr. LCMS indicated the completion of de-protection. A red residue was obtained after removing the volatiles on rotary evaporator, and was suspended (majority dissolved) in 10 mL 1:1 trimethyl orthoformate: MeOH. The resulting mixture was stirred for 2 hrs at room temperature. Yellow solids were precipitated. Desired product (0.38 g, 95% overall yield) was obtained after suction filtration and washing with cold MeOH twice.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8](C)=[CH:7][CH:6]=1)([O-])(=O)=O.[O-:12][C:13]1C=CC=[CH:15][CH:14]=1.[K+].[CH3:20][N:21]([CH3:24])[CH:22]=[O:23]>>[CH3:20][N:21]1[CH2:24][CH:14]([CH2:13][O:12][C:5]2[CH:6]=[CH:7][CH:8]=[CH:10][CH:11]=2)[CH2:15][C:22]1=[O:23]
Reactant: [O-]c1ccccc1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Product: CN1CC(COc2ccccc2)CC1=O

Procedure:
A solution of the resulting tosylate (21.5 g; 0.075 mole) and of potassium phenoxide (10 g; 0.075 mole) in dimethylformamide (150 ml) is refluxed for 2 hrs.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Oc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Oc1ccc2c(c1)CCC2
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 5-hydroxyindan (13.4 g), triethylamine (14.0 ml) and dichloromethane (150 ml) was added 2-methylbenzoyl chloride (15.4 ml) dropwise with constant stirring. The mixture was further stirred under ice-cooling for one hour, after which it was washed with water and dried (MgSO4). The solvent was then distilled off to give 5-(2-methylbenzoyloxy)indan as oil in quantitative yield.
Reaction SMILES: C(OC([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:9][CH2:10][O:11]S(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C.[O:30]1[C:34]2[CH:35]=[CH:36][S:37][C:33]=2[C:32]([C:38]2[CH:39]=[C:40](O)[CH:41]=[CH:42][CH:43]=2)=[N:31]1>>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][NH:8][CH2:9][CH2:10][O:11][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([C:32]2[C:33]3[S:37][CH:36]=[CH:35][C:34]=3[O:30][N:31]=2)[CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)cc1
Reactant: Oc1cccc(-c2noc3ccsc23)c1
Product: Fc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from a mixture of toluene-4-sulfonic acid 2-[tert-butoxycarbonyl-(3-fluoro-benzyl)-amino]-ethyl ester and 3-thieno[2,3-d]isoxazol-3-yl-phenol essentially as described in Example 3, Scheme I, Step F. It is understood by one skilled in the art that the nitrogen may be deprotected by acid hydrolysis, to give the final, desired compound.
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH:7]3[NH:14][C:15]3[C:20]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[CH:19][N:18]=[C:17]4[NH:31][CH:32]=[CH:33][C:16]=34)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2].[H][H]>[Pd].CO.O1CCOCC1>[C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH:7]3[NH:14][C:15]3[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[C:17]4[NH:31][CH:32]=[CH:33][C:16]=34)[CH2:5]1)[CH2:11]2)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)C12CC3CC(C1)C(Nc1c(C(=O)OCc4ccccc4)cnc4[nH]ccc14)C(C3)C2
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)C12CC3CC(C1)C(Nc1c(C(=O)O)cnc4[nH]ccc14)C(C3)C2
Yield: 80.2 %

Procedure:
10% Palladium on carbon (50% wet) (40 mg) was added to a solution of benzyl 4-[(5-carbamoyladamantan-2-yl)amino]-1H-pyrrolo-[2,3-b]pyridine-5-carboxylate (183 mg) in methanol (5 ml) and 1,4-dioxane (5 ml), and hydrogenated under hydrogen atmosphere for 5 hours. Resulting precipitates were dissolved by tetrahydrofuran and filtered out the catalysts. The filtrates were evaporated in vacuo to give 4-[(5-carbamoyladamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (117 mg).
Reaction SMILES: C([BH3-])#N.[Na+].O=[C:6]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:22]([O:29][C:30]([CH:32]([N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([NH:41]C(C(OCC)=O)CCC2C=CC=CC=2)[C:35]1=[O:56])[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:22]([O:29][C:30]([CH:32]([N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]([NH:41][CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:35]1=[O:56])[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@H]1CCCCN(C(C)C(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)C(=O)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)OCc1ccccc1)N1CCCC[C@H](NC(CCc2ccccc2)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 490 mg sodium cyanoborohydride in 3 ml ethanol is added over 2.5 hrs to a solution of 2.43 g t-butyl 2-oxo-4-phenylbutyrate, 850 mg 1-(1-benzyloxycarbonylethyl)-3-(S)-aminoperhydroazepin-2-one hydrochloride (from Isomer A, Example 24) and 267 mg sodium acetate in 10 ml ethanol. The reaction is stirred at room temperature overnight, filtered and concentrated. The residue is partitioned between ethyl acetate and 5% sodium bicarbonate. After drying, concentration of the organic phase affords a residue which is chromatographed over silica gel with hexane-ethyl acetate (7:3) giving the pure diastereomers of 1-(1-benzyloxycarbonylethyl)-3-(S)-(1-t-butoxycarbonyl-3-phenylpropyl)aminoperhydroazepin-2-one.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5]([CH3:24])=[N:6][C:7]2[N:8]([C:11]([CH3:23])=[N:12][C:13]=2[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:9]=1O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:36])=O>>[Cl:36][C:9]1[N:8]2[C:11]([CH3:23])=[N:12][C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[C:7]2[N:6]=[C:5]([CH3:24])[C:4]=1[CH2:3][CH2:2][Cl:1]
Reactant: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCCl)c(C)nc23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(C)c(-c2nc(C)n3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-chloroethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidin-4-ol (200 mg, 0.58 mmol) and N,N-dimethylaniline (0.3 mL) in phosphorus oxychloride (3 mL) was heated under reflux for six hours. After evaporating, 3-aminopentane (2 mL) was added to a solution of the residue in acetonitrile (5 mL), followed by stirring at 80° C. for three hours. Water was added, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-20% ethyl acetate/hexane), to give the title compound (139 mg) as pale yellow crystals.