Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:15]2NCCN[N:16]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C#N)C1C=CC=CC=1.C(Cl)C1C=CC=CC=1>>[C:1]1([CH:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]#[N:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CC(C2=NNCCN2)c2ccccc2)cc1
Solvent: ClCc1ccccc1
Solvent: N#CCc1ccccc1
Product: N#CC(Cc1ccccc1)c1ccccc1

Procedure:
A process for preparing 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine which comprises reacting benzyl cyanide with benzyl chloride to produce 2,3-diphenylpropionitrile and cyclizing the 2,3-diphenylpropionitrile with 2-aminoethylhydrazine in the presence of a catalytic amount of elemental sulfur to give 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine.
Reaction SMILES: Cl[S:2]([NH:5][C:6](=[O:26])[O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:4])=[O:3].[CH2:27]([OH:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>C1COCC1>[C:20]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[O:7][C:6](=[O:26])[NH:5][S:2]([O:39][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:4])=[O:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of [1,1':3',1"-terphenyl]-2'-yl (chlorosulfonyl)carbamate (5.0 g, 12.9 mmoles) in 75 mL THF was added dropwise to a solution of n-dodecyl alcohol (2.4 g, 12.9 mmoles) and triethylamine (1.3 g, 12.9 mmoles) in 100 mL THF at ~15° C. under an atmosphere of N2. The mixture was allowed to warm to room temperature for 16 hours, then concentrated in vacuo and partitioned between H2O and EtOAc. The EtOAc layer was dried with MgSO4 and evaporated to give a white solid. Chromatography (SiO2, 10% EtOAc/hexanes) gave 2.95 g of the title compound, mp 124°-126° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38]Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Yield: 76 %

Procedure:
Using General Procedure A: A solution of {4-[(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.605 g, 2.06 mmol), 1-(tert-butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.804 g, 3.01 mmol), KI (72 mg, 0.43 mmol) and DIPEA (0.70 mL, 4.02 mmol) in CH3CN (10 mL) was heated at 80° C. for 6 hours. Purification of the crude material by column chromatography on silica gel (15:1 CH2Cl2-MeOH) followed by column chromatography on silica gel (NH4OH saturated Et2O) provided 0.82 g (76%) of 2-{[(4-tert-Butoxycarbonylamino-butyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]([F:32])([F:31])[C@:6]([C:9]2[N:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]([NH2:24])=[N:22][C:21]([C:25]([F:28])([F:27])[CH3:26])=[C:20](Cl)[N:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[F:30])([CH3:8])[N:7]=1>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[O:3][CH2:4][C:5]([F:31])([F:32])[C@:6]([C:9]2[N:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]([NH2:24])=[N:22][C:21]([C:25]([F:28])([F:27])[CH3:26])=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[F:30])([CH3:8])[N:7]=1
Reactant: CC(F)(F)c1nc(N)c(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)n2)nc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)c1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)n2)c(N)n1
Reaction time: 2.5 h

Procedure:
To a solution of 3-amino-6-chloro-5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid [6-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide [Example 34] (54 mg, 0.113 mmol) in MeOH/THF (1:1, 10 ml) was added Pd/C 10% (BASF 4505 D/R E, 12 mg) and the mixture was set under an hydrogen atmosphere. After 2.5 h more Pd/C 10% (BASF 4505 D/R E, 11 mg) was added and the hydrogenation continued for another 2.5 h. The reaction mixture was filtered through a pad of Celite, washed with MeOH and the solvent evaporated. The residue was purified by chromatography on silica gel (DCM to DCM/MeOH 9:1) to provide the title compound as yellow foam.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:13][N:12]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[CH:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:39]=1)([CH3:36])[CH3:35]>CN(C=O)C.[Cu]I.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>[CH:34]([O:37][C:38]1[N:39]=[C:40]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[S:13][N:12]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH:3]=2)[CH:41]=[CH:42][CH:43]=1)([CH3:36])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 57.8 %

Procedure:
A mixture of tert-butyl (3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.6 g, 1.0 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (0.429 g, 1.0 mmol) in DMF (10 mL) was bubbled N2 gas for 15 min. To the above mixture, CuI (95 mg, 0.5 mmol.) and Pd(PPh3)4 (12 mg, 0.1 mmol) were added and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The reaction mixture was quenched with H2O (10 mL) and extracted with CHCl3 (2×25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by neutral alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give tert-butyl (3-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.35 g, 57.4%). MS (ESI, pos. ion) m/z: 606.4 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ 9.33 (s, 1H), 8.52 (s, 1H), 8.16-8.08 (m, 2H), 7.97 (d, J=8 Hz, 2H), 7.76 (t, J=7.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 5.52-5.49 (m, 1H), 2.30 (s, 3H), 1.40 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ncccc23)CC1

Procedure:
(6.7 mg, 18%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (25.0 mg, 0.12 mmol) and benzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB+ for C20H19N3O: calculated MH+: 318.16064. Found: 318.16191.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[C:7](/[N:9]=[C:10](\[N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)/[N:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH3:33])[CH2:21][CH2:20]2)=[O:18])[C@@H:13]([C:34](OC)=[O:35])[CH2:12]1)#[N:8].NO>CO>[C:7](/[N:9]=[C:10](\[N:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)/[N:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH3:33])[CH2:23][CH2:24]2)=[O:18])[C@@H:13]([C:34]([NH:2][OH:3])=[O:35])[CH2:12]1)#[N:8]
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)[C@H]2CCN(/C(=N/C#N)N3CCCCC3)C[C@@H]2C(=O)NO)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (1.56573 g, 0.0223062 mol) in anhydrous methanol (6.0 mL) at rt was added 4.37 M of sodium methoxide in methanol (7.64 mL). The reaction mixture was heated at 55° C. for 5 min, cooled to rt, then to 0° C. Filtration afforded a clear solution assumed to be ca. 1.50 M in methanol. To a stirred solution of methyl(3R,4S)-1-[(E)-(cyanoimino)(piperidin-1-yl)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (53.30 mg, 0.0001054 mol) in anhydrous methanol (1.110 mL, 0.02740 mol) at rt was added the above 1.50 M of hydroxylamine in methanol (1.40 mL). The reaction mixture was stirred at rt for 2 h. LCMS showed the reaction was done. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC with 5-95% MeCN/H2O to give the product. MS (ESI): (M+H)+=507.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:36])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:35])[NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:11]=[C:10]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:9]=2[OH:44])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:52][C:53]([O:55][CH3:56])=[O:54]>CN(C=O)C>[CH3:56][O:55][C:53](=[O:54])[CH2:52][O:44][C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][C:12]([C:14](=[O:36])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:35])[NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1
Reactant: O=C(Nc1cccc2ccccc12)OCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCOC(=O)Nc2cccc3ccccc23)cc1-c1cccc(Cl)c1
Yield: 64.7 %

Procedure:
To a stirred solution of 3,3″-dichloro-5′-[6-(naphthalen-1-ylcarbamoyloxy)hexylcarbamoyl]-[1,1′;3′1″]-terphenyl-2′-ol (0.320 g, 0.510 mmol) and K2CO3 (0.078 g, 0.561 mmol) in DMF (10 mL) at room temperature was added dropwise methyl bromoacetate (0.097 mL, 1.02 mmol). After 18 h at this temperature, it was concentrated and then diluted with excess EtOAc (250 mL). The organic layer was washed with 1 N HCl (25 mL), sat. aq. NaHCO3 (25 mL), and brine (25 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (30 to 50% EtOAc/petroleum ether gradient) to afford the product (0.231 g, 65%) as a solid; 1H NMR (DMSO-d6) δ 1.32–1.49 (m, 4H), 1.49–1.73 (m, 4H), 3.23–3.35 (m, 2H), 3.44 (s, 3H), 3.99 (s, 2H), 4.11 (t, J=6.3 Hz, 2H), 7.45–7.63 (m, 10H), 7.69 (s, 2H), 7.73 (d, J=9.4 Hz, 1H), 7.87–7.94 (m, 3H), 8.02–8.12 (m, 1H), 8.61 (t, J=5.5 Hz, 1H), 9.49 (s, 1H); mass spectrum [(+) ESI], m/z 700 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:40])[C:30](=[O:31])[NH:29][C:6]2=[N:7][CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:21](C5CCCCO5)[CH:20]=[N:19][N:18]=4)=[CH:13][C:12]=3[CH3:28])[N:10]=[C:5]2[N:4]1[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O.C(O)C>[CH3:2][C:3]1([CH3:40])[C:30](=[O:31])[NH:29][C:6]2=[N:7][CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[NH:21][CH:20]=[N:19][N:18]=4)=[CH:13][C:12]=3[CH3:28])[N:10]=[C:5]2[N:4]1[CH2:32][CH2:33][CH:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Temperature: 80 °C
Yield: 48 %

Procedure:
6 N Hydrochloric acid in water was added to a stirred mixture of 3,3-dimethyl-6-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one in ethanol at 80° C. The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 70 min. The resulting mixture was filtered and purified using reverse-phase preparatory HPLC (10-65% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate and the acetonitrile removed under reduced pressure. Solids were collected by vacuum filtration, washed thoroughly with water and diethyl ether and dried under high vacuum at 50° C. to give the desired product in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (br. s., 1H), 8.44 (br. s., 1H), 7.96 (s, 1H), 7.90 (d, J=8.59 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=7.81 Hz, 1H), 3.78 (dd, J=2.93, 11.13 Hz, 2H), 3.52-3.64 (m, 2H), 3.23 (t, J=10.93 Hz, 2H), 2.48 (s, 3H), 1.51-1.66 (m, 5H), 1.49 (s, 6H), 1.11-1.26 (m, 2H); MS (ESI) m/z 448.3 [M+1]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[OH:10].Cl.O>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C@H:11]2[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=C1CCC(c2ccc(O)c(F)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc([C@H]2CC[C@H](O)CC2)cc1F
Temperature: 0 °C

Procedure:
0.76 g (20 mmols) NaBH4 was suspended in 30 ml THF under nitrogen and cooled to 0° C. A solution of 4.16 g 4-(3-fluoro-4-hydroxyphenyl)cyclohexanone in 50 ml THF was added dropwise at the same temperature over a period of 15 minutes, and the resulting mixture was stirred at 0° C. until no more of the starting material was present. 10 ml 25% HCl was then added dropwise at a temperature of between 0-10° C., and stirred for a further 30 minutes. The reaction mixture was then poured into 100 ml of water and extracted three times with 50 ml of diethyl ether. The combined organic phases were washed twice with 50 ml of water, dried over magnesium sulphate and filtered. Removal of the solvent and recrystallisation of the residue from isopropanol gave 2-fluoro-4-(trans-4-hydroxycyclohexyl)phenol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2cnccn2)s1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2cnccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-pyrazinyl-2-thiophenecarboxaldehyde (prepared as described in Reference Example 87) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21](F)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]C1C=CC=C(Cl)C=1C[Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([Cl:31])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1c(Cl)cccc1Cl
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1c(Cl)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,6-dichlorobenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=442 @ Rt 3.49 min. major peak.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:28])[C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:28])[C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])=[CH:17][CH:18]=1
Reactant: CN(C(=O)[C@H]1CCCNC1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 84.4 %

Procedure:
4-Fluorobenzoyl chloride (47 mL, 0.40 mmol) was added at 0° C. to a solution of (S)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl-amide hydrochloride (0.11 g, 0.40 mmol) and triethylamine (112 mL, 0.80 mmol) in dichloromethane (3 mL), under nitrogen atmosphere. The reaction mixture was kept under stiffing at R.T. for 2 h, the solvent was evaporated and the residue was diluted with water and ethyl acetate. The phases were separated and the organic layer was washed with HCl 1N (10 mL), with Na2CO3 2M (aq.) (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give 0.121 g of (S)-1-(4-fluoro-benzoyl)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl-amide as a gummy solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: OC1CCNCC1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(N2CCC(O)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 79 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 4-hydroxy-piperidine instead of thiomorpholine to the title compound (SiO2, dichloromethane:methanol=100:0 to 90:10, 197 mg, 79%) which was obtained as an off-white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [O-][N+:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=[N:14][C:4]=2[CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:28][C:3]1[C:4]2[N:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[N:2]=1
Reactant: CC(C)(C)OC(=O)NCCOCCn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2c(N)nc3ccccc3c21
Reaction time: 3 h

Procedure:
A solution of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min period. The reaction mixture was treated with an additional 2 mL of concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 3 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 4.56 g of tert-butyl 2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)[N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+]>CO.O>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=3)[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Yield: 100.3 %

Procedure:
Benzyl 3-(4-(methoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.16 g, 2.32 mmol) and lithium hydroxide (0.15 g, 3.48 mmol) in methanol (10 mL) and water (1 mL) were stirred at 45° C. for 20 h. The reaction was partially evaporated under vacuum, the residue acidified with 6M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and evaporated to give product as a white solid (1.13 g, quant.); 1H NMR (DMSO-d6); δ1.89 (d, J=14 Hz, 2H); 2.27-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.01 (m, 2H); 5.14 (d, 13.6 Hz, 2H); 5.23 (s, 2H); 6.91 (t, J=7.6 Hz, 1H); 6.96 (d, J=8 Hz, 2H); 7.27 (dd, J=7.6
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.