Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH:24]=[O:25])=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1>C1COCC1>[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH:24]([OH:25])[CH3:1])=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(C=O)ccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in THF (3 M, 0.85 mL, 2.56 mmol, 1.3 equiv) was added to a solution of 2-(2-chloro-3-quinolinyl)-5-formyl-1H-indole-1-carboxylate (8-1, 800 mg, 2.0 mmol, 1 equiv) in THF (25 mL) at 0° C., and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between pH 7 phosphate buffer solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 70% EtOAc in hexane) to provide tert-butyl 2-(2-chloro-3-quinolinyl)-5-(1-hydroxyethyl)-1H-indole-1-carboxylate (8-2) as a white foam. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 1H, J=8.8 Hz), 8.18 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.78 (br t, 1H, J=7.1 Hz), 7.64 (s, 1H), 7.61 (br t, 1H, J=7.1 Hz), 7.42 (dd, 1H, J=8.6, 1.5 Hz), 6.66 (s, 1H), 5.05 (m, 1H), 1.58 (d, 3H, J=6.6 Hz), 1.27 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:13]([C:14]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:15])[CH3:12]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc2cc(Br)ccc2o1
Yield: 87.8 %

Procedure:
5-Bromo salicylaldehyde (10.05 g), bromo acetone (8.0 g) and potassium carbonate (13.80 g) were refluxed for 1 hr in 2-butanone (100 ml). 2-Butanone (ca. 50 ml) was evaporated and ice was added. The precipitate was collected by filtration and washed with water and hexane to give the objective compound (10.50 g).
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.[Ni]>[N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ncccc1N1CCCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ncccc1N1CCCCC1
Yield: 62.7 %

Procedure:
A solution of 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile (0.980 g, 5.23 mmol) in MeOH (10 mL) was added to a flask charged with Raney Ni (pre-washed with methanol) (1.0 g) in MeOH (10 mL). After saturated with NH3 gas the mixture was shaken under H2 (40 psi) for 3 h. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (100:5:1 CH2Cl2/MeOH/NH4OH), affording C-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl)-methylamine as a pale yellow oil (0.627 g, 63%). 1H NMR (CDCl3) δ 1.53-1.61 (m, 2H), 1.65-1.74 (m, 4H), 2.82 (t, 4H, J=5.4 Hz), 3.99 (s, 2H), 7.11 (dd, 1H, J=4.8, 8.1 Hz), 7.31 (dd, 1H, J=1.5, 8.1 Hz), 8.27 (dd, 1H, J=1.5, 4.8 Hz).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9]>O.Cl>[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][NH2:1])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(N)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1Cl
Yield: 173.4 %

Procedure:
A solution of sodium nitrite (6 g) in water (50 ml) was added dropwise to a solution of 3-chloro-4-methoxyaniline (10 g) in concentrated hydrochloric acid (30 ml) at 0° C. with stirring. After the addition was completed, the reaction mixture was stirred at the same temperature for 1 hour. A solution of stannous chloride dihydrate (50 g) in concentrated hydrochloric acid (30 ml) was added dropwise at 0° C. The resulting mixture was stirred for 2 hours at the same temperature. The resulting precipitate was collected by filtration, washed with ice water and dried in vacuo at 50° C. to afford (3-chloro-4-methoxyphenyl)hydrazine hydrochloride (11.5 g) as a yellow brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 0.25 h
Yield: 192.2 %

Procedure:
Bis(4-bromophenyl)amine (4.0 g, 12.3 mmol) and phenylboronic acid (4.0 g, 32.7 mmol) were mixed in 250 mL of toluene and 60 mL of ethanol. The solution was bubbled with nitrogen while stirring for 15 minutes. Pd(PPh3)4 (1.4 g, 1.23 mmol) and K3PO4 (13.5 g, 64 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through filter paper and the solvent was then evaporated. The solid was redissolved in nitrogen-purged hot toluene and was filtered through a Celite®/silica pad when the solution was still hot. The solvent was then evaporated. The white crystalline solid was washed by hexane and air dried to obtain 3.8 g of product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O.[CH2:22]([N:27](CCCCC)[C:28](=O)[C:29]1C=C(C=O)[CH:32]=[CH:31][C:30]=1OC)[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:28]([N:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8](=[O:10])[C:7]1[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=[CH:14][C:6]=1[O:5][CH2:4][C:3]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=1[F:1])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Reactant: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)O)c1
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OCc1ccc(F)cc1F

Procedure:
N,N-Di-n-pentyl-2-(2,4-difluorobenzyloxy)-5-formylbenzamide was prepared from 2-(2,4-difluorobenzyloxy)-5-formylbenzoic acid (200 mg, 1 eq) using the same procedure as for N,N-di-n-pentyl-2-methoxy-5-formylbenzamide. The product was obtained as a pale brown oil (442 mg, 99%). 1H NMR (CDCl3) δ9.89 (s, 1H, O═C—H), 5.22 (d, 1H, CH2Ar), 5.10 (d, 1H, CH2Ar), 3.74 (m, 1H, NCH2), 3.14 (m, 1H, NCH2), 3.05 (m, 2H, NCH2).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[C:40]([F:41])([F:42])[F:43]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 49 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.30 (s, 1H), 8.94 (d, 1H), 8.47 (d, 3H), 7.72 (dd, 2H), 7.28 (t, 1H), 6.59 (s, 1H), 5.41 (d, 1H), 3.13 (dd, 1H), 3.03 (dd, 1H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ncn1

Procedure:
22.4 g (0.15 mol) of 4,6-dichloropyrimidine were introduced into 250 ml of methanol. 27 g of a 30% strength sodium methylate solution were added dropwise at 0° C. After concentration, the mixture was worked up using a water/methylene chloride mixture. 15.0 g (69.2% of theory) of yellow crystals were obtained; m.p. 32°-34° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.CCN(C(C)C)C(C)C>O>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: c1cn[nH]c1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(-n2cccn2)n1
Temperature: 120 °C
Yield: 81.9 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (0.49 mg, 1.22 mmol), 1H-pyrazole (1.0 g, 14.7 mmol), and DIPEA (3 mL) was heated to 120° C. for 40 min, cooled to 20° C., and diluted with water (50 mL). The resulting precipitate was collected by filtration, washed with water, and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (4:1), gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole (428 mg, 82%): mp (CH2Cl2/hexanes) 274-277° C.; 1H NMR (DMSO-d6) δ 8.79 (dd, J=2.8, 0.5 Hz, 1H), 8.14 (dd, J=8.3, 0.5 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.88 (t, J=52.8 Hz, 1H), 7.49 (t, J=8.2 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.70 (dd, J=2.8, 1.5 Hz, 1H), 4.01 (m, 2H), 4.00 (s, 3H), 3.93 (m, 2H), 3.80-3.75 (m, 4H); Anal. Calcd. for C19H18F2N8O2: C, 53.3; H, 4.2; N, 26.2. Found: C, 53.1; H, 4.1; N, 25.9%.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Br:12])=[CH:7][C:6]=2[Cl:13].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[C:16]([Si:19]([O:14][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[C:6]([Cl:13])[CH:7]=[C:8]([Br:12])[CH:9]=2)[CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc2c(Cl)cc(Br)cc2cc1Br
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(Cl)cc(Br)cc2cc1Br

Procedure:
The title compound was prepared by reacting 3,6-dibromo-8-chloro-2-naphthol (3.00 g, 8.92 mmol) with TBDMS-Cl (1.75 g, 150.7 mmol) according to method F to yield 3.36 g (84%) of a white solid: mp 58–64° C.; 1H NMR (CDCl3): δ 0.34 (6H, s), 1.08 (9H, s); 7.57 (1H, s), 7.62 (1H, d, J=1.72 Hz), 7.75 (1H, d, J=1.24 Hz), 7.97 (1H, s); MS (ESI) m/z 333/335/337 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([N+:32]([O-])=O)=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Sn](Cl)Cl>CCO>[NH2:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[CH2:13][CH2:12]3)[C:18]=2[CH:31]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Yield: 62.1 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (120 mg) in EtOH (15 ml) were added tin (II) chloride (190 mg), and the mixture was heated to reflux for 1 hour. The was distilled off under reduced pressure. The residue was added ethyl acetate and sodium aqueous to neutralize. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (95:5) to give the titled compound (70 mg).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.CO[CH:14](OC)[CH2:15][Cl:16].C([O-])(O)=O.[Na+].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[N:26]=1>O.C(O)C>[Cl:16][C:15]1[N:26]2[CH:27]=[CH:28][N:24]=[C:25]2[CH:30]=[CH:29][CH:14]=1
Reactant: COC(CCl)OC
Reactant: Nc1cccc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cccc2nccn12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
To a solution of pTSA (103 mg, 0.65 mmol) in water (5 ml) and ethanol (20 ml) was added chloroacetaldehyde dimethyl acetal (2.0 g, 16.0 mmol) at room temperature. The reaction was stirred at 65° C. for 30 minutes and then cooled to room temperature and a saturated solution of NaHCO3 was added dropwise until pH 7 was reached. 2-Amino-6-chloropyridine (2.1 g, 16 mmol) in 4:1 ethanol:water (20 ml) was then added and the reaction was heated at reflux for 3 hours. After cooling and concentrating at reduced pressure, the residue was purified by FCC (98:2 DCM/MeOH) to give the title compound (850 mg, 36%) as brown oil.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3([CH:12]([NH2:13])[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[CH2:3][O:2]1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CC3(COC3)C2)CCC1
Product: NC(c1ccccc1)C1(N2CC3(COC3)C2)CCC1

Procedure:
The title compound, yellow oil, MS: m/e=259.1 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-cyclobutanecarbonitrile (intermediate AF) and phenyllithium.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[C:13]1(=[O:18])[O:17][CH:15]([CH3:16])[CH2:14]1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:15]([CH3:16])[CH2:14][C:13]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1CC(=O)O1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C

Procedure:
4-Nitrophenol (34.78 g, 0.25 mol) was added to a solution of 10 g (0.25 mol) sodium hydroxide in 100 ml water and the solution heated at reflux for 15 minutes. To the solution at reflux, 20.4 ml (0.25 mol) betabutyrolactone was added dropwise over a 1.5 hour period. The reaction was cooled to 23° C. and extracted with 2×150 ml diethyl ether. The combined ether layers were extracted with 4×140 ml saturated sodium bicarbonate solution and the bicarbonate then acidified with 60 ml concentrated hydrochloric acid and back-extracted with 200 ml diethyl ether. The ether back extract was washed with 50 ml water and 50 ml brine, and dried over magnesium sulfate. Concentration in vacuo gave the product as a yellow oil, 31.2 g (55%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[C:16]([S:20]([NH:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](O)=O)[CH2:26][CH2:25]1)(=[O:22])=[O:21])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([S:20]([NH:23][C@@H:24]1[CH2:25][CH2:26][C@H:27]([C:30]2[NH:8][C:7]3[C:2](=[N:3][C:4]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)=[N:5][CH:6]=3)[N:1]=2)[CH2:28][CH2:29]1)(=[O:22])=[O:21])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1cnc(-c2ccc(F)cc2)nc1N
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](c2nc3nc(-c4ccc(F)cc4)ncc3[nH]2)CC1

Procedure:
By following the same procedure as described in Example 1 except that use was made of 4,5-diamino-2-(4-fluorophenyl)pyrimidine and cis-4-tert-butylsulfonylaminocyclohexanecarboxylic acid in place of 4-trifluoromethyl-1,2-phenylenediamine, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH:42][CH:43]1[CH2:46][NH:45][CH2:44]1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:45]4[CH2:46][CH:43]([OH:42])[CH2:44]4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: OC1CNC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CC(O)C4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 3-hydroxyazetidine. MS (ES+): m/z 651.24 (100) [MH+]; HPLC: tR=0.91 min (UPLC, purity).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1>C1COCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCC4CC[SiH](Cl)CC4)CC3)cc2)cc1
Reactant: CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(C#N)cc4)cc3)CC2)CC1

Procedure:
12.5 g (0.1 mol) of n-propyl bromide was dripped into a mixture of 2.5 g (0.1 mol) of magnesium and 500 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 42 g (0.1 mol) of 4-(trans-4-(2-(4-chloro-4-silacyclohexyl)ethyl)cyclohexyl)-4'-cyanobiphenyl to obtain 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-cyanobiphenyl. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 32.8 g (yield 76.4%) of the trans isomer.
Reaction SMILES: [C:1]12([C:11]3[C:12](=[O:22])[NH:13][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.I[CH3:24]>CN(C=O)C>[C:1]12([C:11]3[C:12](=[O:22])[N:13]([CH3:24])[N:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=c1[nH]n(-c2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C23CC4CC(CC(C4)C2)C3)cn1-c1ccccc1
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A sealable tube was charged with 4-adamantan-1-yl-1-phenyl-1,2-dihydro-pyrazol-3-one (0.05 g), iodomethane (0.036 g) and DMF (1 mL) and purged with argon and sealed. The reaction vessel was immersed into a heated oil bath at 110 degrees C. for 16 hours. The reaction vessel was then cooled and opened carefully. The reaction mixture was diluted with EtOAc and aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with further EtOAc and the combined organic layers were washed with sodium thiosulfate. The phases were then dried over sodium sulfate, filtered and reduced in vacuo. The crude gum was chromatographed by adsorption onto silica gel and subjection to Isco Combiflash chromatography. Evaporation of the desired fractions afforded the desired product 4-adamantan-1-yl-2-methyl-1-phenyl-1,2-dihydro-pyrazol-3-one (0.035 mg) as a white solid. MS (ESI+): 309.4 [M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(C)=O

Procedure:
To a suspension of about 46.57 g of L-serine methyl ester hydrochloride in about 3 liters of chloroform was added about 84 ml of triethylamine. This mixture was stirred until solution was complete, then about 21 ml of acetyl chloride was added dropwise. The mixture was then stirred under argon for about 2 days and the chloroform removed under reduced pressure. The residue was suspended in ethanol, filtered through a sintered glass funnel and the ethanol removed, giving about 49 g of the desired title compound [α]D26 =+36°±1° (CHCl3, 1.039%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=3)[NH:10][C:9]2=[O:14])=[CH:16]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ccccc13)C(=O)N2

Procedure:
5-Aminosulfonyl-2-oxindole was condensed with indole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3c2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A solution of 3-iodo-5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (870 mg, 2.12 mmol) in anh. THF (10 ml) was cooled to 0° C. and NaH (60% dispersion, 130 mg, 3.18 mmol) was added. After 20 min tosyl chloride (450 mg, 2.33 mmol) was added and the mixture was allowed to warm to room temperature. After 3 hrs the mixture was cooled to 0° C. and quenched by the addition of 0.5 N HCl. The product was extracted with DCM and purified by silica gel chromatography using DCM as an eluent affording 648 mg (54%). 1H NMR (CDCl3, 300 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.12 (d. J=8.4 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 6.73 (s, 2H), 3.94 (s, 6H), 3.90 (s, 3H), 2.39 (s, 3H).