Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26]C(Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex: ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5](N)[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.C(N(CC)CC)C>[CH2:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: Nc1c2c(cc3c1CCC3)CCC2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Yield: 113.8 %

Procedure:
To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (77 grams) in tetrahydrofuran (1.5 L) and triethylamine (68.3 mL) was added triphosgene (43.9 grams) in one portion. The mixture was heated to reflux for 1/2 hour, then cooled to room temperature. The tetrahydrofuran was removed under reduced pressure, and the residue was taken up in pentane and filtered through a plug of silica gel. Removal of the pentane in vacuo afforded 80 grams of a white solid, m.p. 35.0-36.2° C.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])(=[O:14])=[O:13].Cl.N1C=CC=CC=1>C(#N)C>[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[CH:1]1)(=[O:14])=[O:13]
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)CCOCCn1cnc2cnc3ccccc3c21
Reaction time: 0.33 h
Yield: 67.9 %

Procedure:
Triethyl orthoformate (2 mL, 12 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.1 g, 10 mmol) in acetonitrile (50 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 20 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide a viscous oil. The oil was triturated with ethyl acetate. The resulting solid was isolated by filtration and washed with ethyl acetate to provide 2.17 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as an off-white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([NH2:27])[N:21]=1.Cl>CS(C)=O>[NH2:19][C:20]1[N:25]=[C:24]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[CH:15][CH:16]=2)[CH:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
N-(4-Hydroxymethyl-benzyl)-2,2,2-trifluoro-acetamide (12.0 g, 52 mmol) is dissolved in 80 ml dry DMSO, and NaH (4.08 g, 102 mmol, suspension 60% in mineral oil) is added in portions over 30 min under an argon atmosphere. After stirring at room temperature for 1 h, 2,6-diamino-4-chloropyrimidine (7.52 g, 52 mmol) is added and the reaction mixture heated to 60° C. over night. After cooling to room temperature, the mixture is poured into 1 L of 1 N HCl, and the product extracted with ethyl acetate (500 mL). The combined organic phases are washed with water and brine, dried over MgSO4, and the solvent evaporated. The residue is purified by flash column chromatography (ethyl acetate/methanol 100:0 to 80:20) to yield the title compound as a colorless solid (4.7 g, 13.78 mmol, 27%). 1H-NMR (400 MHz, DMSO-d6): δ=9.99 (t, J=6.1, 1H, CONH), 7.34 (d, J=8.1, 2H, ArH), 7.26 (d, J=8.1, 2H, ArH), 6.02 (s br, 2H, NH2), 5.89 (s br, 2H, NH2), 5.16 (s, 2H, OCH2), 5.01 (s, 1H, 4-H), 4.36 (d, J=6.1, 2H, CH2NCO) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:17]=1[N+:24]([O-:26])=[O:25].CCOC(C)=O.O>CN(C=O)C>[CH2:7]([O:14][C:20]1[CH:21]=[C:16]([F:15])[C:17]([N+:24]([O-:26])=[O:25])=[C:18]([F:23])[CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Potassium carbonate (544 mg, 3.94 mmol) and benzyl alcohol (0.3 ml, 2.8 mmol) were added to a solution of 2,4,6-trifluoronitrobenzene (500 mg, 2.8 mmol) in DMF (5 ml). This mixture was stirred at RT overnight. Work up (EtOAc/H2O) afforded the title compound (521 mg) as a yellow liquid which was used in the next step without fuRTher purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccc([N+](=O)[O-])cc2)c1
Yield: 35 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-4-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-[2-(4-nitro-phenyl)-ethyl]-9H-purin-6-ylamine: Yield 35%, 1H NMR (DMSO-d6) δ 8.18 (s, 1H), 8.0 (d, J=8.8 Hz, 2H), 7.46 (bs, 2H), 7.26 (d, J=8.8 Hz, 2H), 6.96 (d, J=9.2, 1H), 6.77 (dd, J=8.8, 3.2 Hz, 1H), 6.27 (d, J=3.2 Hz, 1H), 4.50 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.56 (s, 3H), 3.22 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 453.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH2:26]([N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH3:27]
Reactant: CCNc1ccccn1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccn1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (150 mg, 0.36 mmol), ethyl-pyridin-2-yl-amine (131 mg, 1.08 mmol), BOP (207 mg, 0.47 mmol), DIEA (400 μL, 2.16 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-pyridin-2-yl-amide: MS m/z: (M+H) 519.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22]I)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:44][CH:43]=2)[OH:41])=[C:37]([OH:39])[CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:40]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:44][CH:43]=2)[OH:41])=[C:37]([CH:38]=1)[O:39][CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:16][CH:17]=1)=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Oc1cc(OCc2ccccc2)ccc1C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(CI)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1cc(OCc2ccccc2)ccc1C(O)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Yield: 59.8 %

Procedure:
Potassium carbonate (0.165 g, 1.2 mmol) was added to a solution of 1-(4-benzyloxy-phenyl)-2-iodo-ethanone (P4) (0.352 g, 1 mmol) and 5-benzyloxy-2-[(4-benzyloxy-phenyl)-hydroxy-methyl]-phenol (P3) (0.412 g, 1 mmol) were in 40 mL of dry acetone and the mixture was refluxed for 6 hr. After completion of reaction (TLC), the solvent was evaporated and the residue extracted with EtOAc:water (3×40 mL). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was dissolved in EtOAc and chromatographed over silica using hexanes: EtOAc (4:1) to give (0.381 g, 60%) yellowish solid product T3. 1H NMR (400 MHz, CDCl3) δ, 7.88 (d, 2H , J=8.8 Hz, Ar—H2/6), 7.41-7.29 (m, 17H, 2×Ar—H, 3×C6H5), 7.07(d, 1H, J=8.8 Hz, 8.4 Hz), 7.02(d, 2H, J=8.8 Hz, Ar—H3/5), 6.92(d, 2H, J=8.8 Hz, 2×Ar—H), 6.54(dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H4′), 6.5 (d, 1H, J=2.4 Hz, Ar—H6′), 6.04 (d, 1H, J=5.6 Hz, CH—OH), 5.24(m, 2H2O—CH2), 5.13 (s, 2H, PhCH2), 5.04 (s, 2H, PhCH2), 5.0 (s, 2H, PhCH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[C:63]1([NH2:66])[CH2:65][CH2:64]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:66][C:63]3([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=4[C:56]([F:55])([F:67])[F:68])[CH2:65][CH2:64]3)=[O:21])=[CH:17][CH:16]=2)[N:10]=1
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1(c2ccccc2C(F)(F)F)CC1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 13.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.290 mmol), THF (10 mL), di-isopropyl ethyl amine (10.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.035 g, 0.350 mmol) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 2H), 1.31 (s, 2H), 7.59 (d, J=7.2 Hz, 2H), 7.65-7.68 (m, 4H), 7.82 (d, J=12.0 Hz, 2H), 7.88-8.02 (m, 3H), 8.77 (s, 1H), 12.60 (br s, 1H); MS (m/z): 517.03 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:23]=1[C:24](Cl)=[O:25].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:32][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:22]([O:21][CH3:20])[C:23]=1[C:24]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:25]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2c(OC)cccc2OC)cc1
Reaction time: 6 h
Yield: 60 %

Procedure:
To a well-stirred solution of 2-(4'-methoxyphenyl) - 6-methoxybenzo[b]thiophene (0.500 g, 1.85 mmol) and 2,6-dimethoxybenzoyl chloride (1.11 g, 5.56 mmol) in CH2Cl2 (40 mL) was added AlCl3 (0.986 g, 7.40 mmol) portion-wise over a 15 minute period. After 6 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 EtOAc/hexane) afforded the title compound (0.484 g, 1.11 mmol, 60%) as an off-white solid. Recrystallization (hexane/ethanol) afforded a highly pure, crystalline sample with mp 146°-152° C.: 1H-NMR (CDCl3, 360 Mhz): δ=8.54 (dd,J=9.1,0.3 Hz, 1H, ArH), 7.25 (d,J=2.1 Hz, 1H, ArH), 7.12 (d,J=8.8 Hz, 2H, ArH), 7.10 (dd,J=9.0,2.5 Hz, 1H, ArH), 6.98 (t,J=8.4 Hz, 1H, ArH), 6.58 (d,J=8.8 Hz, 2H, ArH), 6.20 (d,J=8.4 Hz, 2H, ArH), 3.88 (s,3H, --OCH3), 3.73 (s,3H, --OCH3), 3.60 (s,6H, --OCH3); 13C-NMR (CDCl3, 90 Mhz): δ=190.3, 159.5, 157.5, 157.3, 151.3, 139.3, 132.9, 131.9, 130.8, 130.5, 126.4, 125.7, 120.3 115.0, 112.6, 103.9, 103.6, 55.6, 55.5, 55.3. HRMS (EI) M30 calcd for C25H22O5S 434.1188, found 434.1188.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19]N)=[CH:17][C:4]1=2.[BH3-][C:22]#[N:23].[Na+].[C:25](O)(=O)C>C(#N)C.C=O>[ClH:1].[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][N:23]([CH3:22])[CH3:25])=[CH:17][C:4]1=2
Reactant: [BH3-]C#N
Reactant: NCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.8 g (0.011 m) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethylamine of Example 6 in 60 ml of acetonitrile and 2.7 ml of 37% aqueous formaldehyde (0.1 m), 2.05 g (0.033 m) of NaBH3CN was added. There was a slightly exothermic reaction. Glacial acetic acid (2 ml) was added over 10 minutes and the reaction was stirred at ambient temperature for 2 hours. An additional 2 ml of glacial acetic acid was added and stirring was continued for 30 minutes. The solvent was evaporated under reduced pressure and the residue was treated with 60 ml of 2N KOH. The resulting mixture was extracted three times with ether. The combined ether extracts were washed with 60 ml of 0.5N KOH and then extracted three times with 1N HCl. The aqueous acidic extracts were combined and neutralized with solid KOH and then extracted with ether. The dried (Na2SO4 ) organic phase was filtered and ethereal HCl was added to precipitate 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N,N-dimethylethylamine hydrochloride, 1.4 g (40%), m.p. 175°-176° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:31])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
Deoxycholic acid (0.54 g, 1.4 mmol) in THF (10 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (0.60 g). The compound would not recrystallise, although gas chromatography showed the product to be 99% pure. The product was further purified by preparative silica tlc. (solvent system: EtOAc/CH2Cl2 /AcOH--10:10:1) to afford pure methyl deoxycholate2 (0.45 g, 80%) as a foam: 1H NMR (60 MHz; CDCl3) δ0.67 (3H, s, 18-CH3), 0.92 (3H, s, 18-CH3), 2.18 (2H, s [exchanges on adding D2O], 3α and 12α OH's), 3.2-3.7 (1H, m. 3β-H), 3.65 (3 H, s, --OMe), 3.8-4-1 (1H, m, 12β-H); IR (nujol mull) 3368 (OH's), 1740 (C=O) cm-1 ; MS: Found m/z 388.2951; C25H40O3 (M-H2O) requires 388.2977.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 1-(4-nitrophenyl)ethanone (15 g, 90.8 mmol), malononitrile (6 g, 90.8 mmol), ammonium acetate (7 g, 90.8 mmol) and acetic acid (10 mL) in benzene (200 mL) was stirred at reflux overnight in a flask equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to provide 9.42 g of the desired product. Rf=0.33 (25% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:15]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. After reaction completion (the reaction being complete when 3 mole equivalents of hydrogen have been reacted), the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline as a white solid (120.6 g, 98%); NMR Spectrum (CDCl3): 2.11 (s, 3H), 2.50 (s, 3H), 6.51 (d, 1H), 6.58 (s, 1H), 6.75 (d, 1H), 6.98-7.03 (m, 2H), 8.18 (s, 1H); Mass spectrum: MH+ 215.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[NH:12][CH:13]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[NH:27][N:28]=[CH:29][C:22]=12.CCN(CC)CC.CC(O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:21]3[N:26]=[CH:25][N:24]=[C:23]4[NH:27][N:28]=[CH:29][C:22]=34)[CH2:16][CH2:15]2)=[N:12][CH:13]=1
Reactant: Clc1ccc(-c2c[nH]c(C3CCNCC3)n2)c(Cl)c1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: Clc1ccc(-c2cnc(C3CCN(c4ncnc5[nH]ncc45)CC3)[nH]2)c(Cl)c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Heat a mixture of 4-(4-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidine (270 mg, 0.91 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (280 mg, 1.82 mmol), Et3N (0.63 mL, 4.5 mmol), and 2-propanol (10 mL) at 90° C. overnight under N2. Cool the mixture to room temperature and pour into water (100 mL). Extract the mixture with CH2Cl2 (2×200 mL), combine the organic layers, and wash with water (50 mL). Dry (Na2SO4) the organic layer, filter the mixture, and concentrate the filtrate in vacuo. Purify the residue by silica gel chromatography (25 g of SiO2, elute with CH2Cl2/CMA 4:1, 1000 mL) to provide 4-(4-(5-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine (304 mg, 80%). Add hydrochloric acid (2.0 M aqueous, 0.36 mL, 0.72 mmol) to a suspension of 4-(4-(5-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 0.72 mmol) in methanol (7 mL). Concentrate the mixture in vacuo to dryness. Dissolve the residue in methanol (2 mL) and add diethyl ether (50 mL) to form a precipitate. Filter the precipitate, and wash the filter cake with Et2O. Dissolve the solid in methanol (10 mL) and remove the solvent in vacuo to dryness to provide 4-(4-(5-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (210 mg, 65%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:12])[CH2:10]Cl)[CH:5]=[CH:6][CH:7]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[Na+].[I-]>CN(C=O)C.CCOCC>[N:13]([CH2:10][CH:9]([OH:12])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:14]=[N-:15]
Reactant: OC(CCl)Cc1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(O)Cc1cccc(Br)c1
Temperature: 75 °C

Procedure:
To a solution of 1-(3-bromophenyl)-3-chloropropan-2-ol (8.49 g, 34.0 mmol) in anhydrous DMF (100 mL) under N2 was added NaN3 (11.05 g, 170.0 mmol) and NaI (cat., 0.75 g, 5.0 mmol). The mixture was heated at 75° C. overnight. After cooling to room temperature, the mixture was diluted with ether and washed with water and brine. The solution was dried over Na2SO4 and concentrated under reduced pressure. The product was dried in a vacuum oven at 40° C. for 2 h to give 1-azido-3-(3-bromophenyl)propan-2-ol as a yellow oil which was used without purification. Yield (8.6 g, 98% crude).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[S:25][CH:26]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[S:25][C:26]=2[Br:1])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2csc3cc(F)ccc23)CC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2c(Br)sc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
In an alternative procedure, add N-bromosuccinimide (1.319 g, 6.62 mmol) to a stirring solution of 4-(6-fluoro-benzo[b]thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 46a) (2.226 g, 6.62 mmol) in CCl4 and reflux for 2 h. Allow cooling to room temperature and filter. Evaporate the solvent and purify the residue by chromatography over silica gel (EtOAc/heptane, 9:1) to obtain 2.34 g (94%) of oil.