Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:9]([CH:56]([CH3:58])[CH3:57])[CH2:10][C@H:11]([OH:55])[C@@H:12]([NH:20][C:21](=[O:54])[C@@H:22]([NH:36][C:37](=[O:53])[C@@H:38]([CH2:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:23][C:24]1[N:25](C(OC(C)(C)C)=O)[CH:26]=[N:27][CH:28]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C@H:9]([CH:56]([CH3:58])[CH3:57])[CH2:10][C@H:11]([OH:55])[C@@H:12]([NH:20][C:21](=[O:54])[C@@H:22]([NH:36][C:37](=[O:53])[C@@H:38]([CH2:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
0.4 g (0.5 mmol) of (S)-N-[(1S,2S,4S)-4-benzoyl-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-3-t-butoxycarbonylimidazole-4-propionamide is dissolved in 5 ml of methylene chloride and treated with 2 ml of 90% trifluoroacetic acid and stirred at room temperature for 4 hours. Thereafter, the reaction mixture is poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extracts are dried over potassium carbonate and evaporated under reduced pressure. Chromatography of the residue on 8 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.087 g of (S)-N-[(1S,2S,4S)-4-benzoyl-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl]hyrocinnamamido]imidazole-4-propionamide as an amorphous solid, MS: 699 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCNCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine (9.2 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-allyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH:15]3[CH2:20][NH:19][CH2:18][CH2:17][N:16]3[CH3:21])[O:12][N:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[OH-].[Na+]>ClCCl>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:19]2[CH2:18][CH2:17][N:16]([CH3:21])[CH:15]([C:13]3[O:12][N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[N:14]=3)[CH2:20]2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCNCC1c1nc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(F)cc2)CC1c1nc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-piperazine dihydrochloride (0.285 g, 0.86 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (374 mL, 2.7 mmol) and 4-fluorobenzoyl chloride (102 mL, 0.86 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred for 2 h. NaOH 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with NaOH 1N (6 mL) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. Purification of the crude by flash chromatography (silica gel, eluent: DCM/MeOH/NH4OH 99/1/0.1) afforded (4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-piperazin-1-yl}-methanone (0.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:33][CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42][CH2:43][CH:34]2[CH3:33])=[O:9])=[CH:10][C:11]([F:14])=[CH:12][N:13]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: CC1CCc2ccccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC1CCc2ccccc2N1C(=O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Temperature: 120 °C
Yield: 22.2 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (36.3 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 120° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 11.5 mg (22%) of the title compound. MS (ISP): 430.8 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][OH:9])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.CCN(CC)CC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3]1
Reactant: CN1CCCC(CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 2.07 g (16 mmol) 1-methyl-3-piperidinemethanol, 3.35 g (18 mmol) p-toluensulfonyl chloride, 0.58 g (5 mmol) 4-dimethylaminopyridine and 2.23 mL (16 mmol) NEt3 in 30 mL DCM was stirred for 2 h at room temperature. The mixture was washed with water and evaporated to dryness to yield 4.5 g (99%) of the title compound as yellow oil which was used without further purification. MS(m/e): 284.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:22]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
N-(4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.180 g, 0.52 mmol) was dissolved in a mixture of 3:1 ethanol/water (4 ml) with stirring. Then iron (0.160 g, 2.8 mmol) and ammonium chloride (0.016 g, 0.30 mmol) was added to the mixture. The mixture was placed in a pre-heated oil-bath (80° C.) for 1 hour. The oil bath was removed, and the mixture was allowed to cool to ambient temperature. The mixture was filtered through filter diskette. The flask was rinsed with methanol (3×10 ml), and the combined filtrate was evaporated in-vacuo. The residue was diluted with dichloromethane and 1N NaOH (2 ml). The organic were extracted with dichloromethane (3×10 ml), dried over sodium sulfate, filtered and concentrated in vacuo. to give the desired product N-(4-(4-amino-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.125 g, 0.4 mmol, 76% yield) as a tan oil. MS (ESI pos. ion) m/z: 317 (MH+). Calc'd exact mass for C16H17FN4O2: 316. 1HNMR (300 MHz, CDCl3): 1.96 (s, 4H), 3.44 (s, 4H), 6.52 (d, J=3.07 Hz, 2H), 6.96 (s, 1H), 7.26 (s, 1H), 7.67 (s, 1H), 8.01 (d, J=5.70 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][N:29]=[N+]=[N-])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][NH2:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CN=[N+]=[N-])c2)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CN)c2)c1
Temperature: 25 °C

Procedure:
3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethyl azide is dissolved in ethanol, and a catalytic amount of PtO2 is added. The reaction flask is attached to a H2 balloon by way of a three-way stopcock, and the atmosphere is exchanged. The mixture is stirred at room temperature. The reaction is followed by TLC and terminated by replacing the atmosphere with N2 when the starting material has disappeared. The catalyst is removed by centrifugation or filtration over a filter membrane. The solution is evaporated and the residue used directly in the following step. If desired, the product can be purified by CC on silica gel eluting with CH2Cl2/methanol/Et3N or CH2Cl2/methanol/conc. aqueous NH3, or on deactivated basic alumina with CH2Cl2/methanol.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][C:33]([CH3:38])([CH3:37])[CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][O:34][C:33]([CH3:37])([CH3:38])[CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: CC1(C)CC(CCCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCOC(C)(C)C1

Procedure:
Prepared similarly to Intermediate 223 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1.5 hours at 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)c1c(N)ccc2c1CCn1nccc1-2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCn1nccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of methyl 8-amino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 22, 0.060 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.081 g) in pyridine (2 mL) and DCM (4 mL) was stirred at room temperature overnight. A further amount of 2-bromo-4-fluoro-benzenesulfonyl chloride (0.010 g) was added and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM and washed with 1M hydrochloric acid, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino)-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.088 g) as a glass.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[N:30](COCC[Si](C)(C)C)[N:29]=[CH:28][C:27]=1B(O)O>>[CH:20]1([CH:16]([N:5]2[C:4]3[N:3]=[C:2]([C:27]4[CH:28]=[N:29][NH:30][C:26]=4[C:22]4[S:21][CH:25]=[CH:24][N:23]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH3:17])[CH2:19][CH2:18]1
Reactant: C[Si](C)(C)CCOCn1ncc(B(O)O)c1-c1nccs1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3cn[nH]c3-c3nccs3)nc2N1C(C)C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 5, with Intermediate SS instead of Intermediate B and with 5-(thiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ylboronic acid (Boronic Acid 1) instead of pyridin-4-ylboronic acid. The resulting coupling product is then deprotected by the method described in Example 331 to give the title compound. LCMS: 410.1 m/z (M+H)+; ret. Time: 7.64 min. (Analytical Method C).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]3[N:12]([CH3:13])[C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[N:9]=3)[CH:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(-c2cc(Br)ccc2F)nc2ccccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: Cn1c(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2F)nc2ccccc21
Temperature: 85 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
2-(5-Bromo-2-fluoro-phenyl)-1-methyl-1H-benzoimidazole (2.10 g, 6.9 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.16 g, 8.3 mmol), cesium carbonate (3.14 g, 9.6 mmol) rac-2,2′ bis(diphenylphosphino)-1,1′-binaphtyl (BINAP) (0.17 g, 0.28 mmol) and tris-(dibenzilideneacetone)dipalladium(0) (0.06 g, 0.07 mmol) were placed in a Schlenk tube and purged by repeated nitrogen/vacuum cycles for 10 minutes. Dry toluene (13 mL) was added and the reaction was stirred at 85° C. for 24 h. Reaction was cooled to room temperature, diluted with AcOEt (20 mL) and washed with water (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% cyclohexane to cyclohexane 2:AcOEt 1) to afford 1.14 g of the starting material and 0.70 g of the title compound (54%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH3:2].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CCOCCNC(=O)c1ccc(Cl)nn1
Product: CCOCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-ethoxyethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (24.8% yield). 1H NMR (500 MHz, CDCl3) δ 8.18, 8.07, 7.76, 7.65, 7.58, 7.38, 7.00, 4.07, 3.90, 3.83-3.65, 3.60, 3.52, 3.36, 1.20. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [S:1]1[C:5]([CH2:6]O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.S(Cl)([Cl:14])=O>>[Cl:14][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2ccccc2s1
Product: ClCc1cc2ccccc2s1

Procedure:
A solution of benzo[b]thiophen-2-yl-methanol (1 eq.) in thionyl chloride was stirred at 20° C. for 1 h. The crude was concentrated under reduced pressure then partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloromethyl-benzo[b]thiophene, used as such without further purification.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:11][CH2:12]2)[CH:9]=[CH:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pt]>[C:1]1([C:7]23[CH2:12][CH2:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:9][CH2:8]2)[CH2:13][CH2:14]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CCOC(=O)C12C=CC(c3ccccc3)(CC1)CC2
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Yield: 83.9 %

Procedure:
Ethyl 4-phenylbicyclo[2.2.2]oct-2-ene-1-carboxylate (Intermediate 3; 26.3 g, 102.5 mmol) in absolute ethanol (600 mL) and 10% Pt on carbon (2.4 mg) were stirred under a balloon of hydrogen at ambient temperature overnight. The reaction mixture was filtered and the solvent removed under reduced pressure to leave a colourless oil which rapidly formed a white solid (22.179 g, 85.96 mmol, 84%) 1H NMR (CDCl3) δ 1.25 (3H, t), 1.83-1.96 (12H, m), 4.12 (2H, q), 7.15-7.20 (1H, m), 7.28-7.31 (4H, m); GC-MS EI m/e M+ 258.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:17][N:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnnc1-c1cnc2ccccn2c1=O
Yield: 50.4 %

Procedure:
A mixture of 4.28 g (0.02 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine; 100 ml of dimethylformamide, 2.76 g (0.02 moles) of anhydrous potassium carbonate and 25 ml (0.04 moles) of methyl iodide was stirred at 75°-80° C. for 1 hour. The yellow suspension gradually dissolved and at the end of the reaction an orange-colored solution was obtained. The warm reaction mixture was filtered, cooled down and the precipitating crystals were collected. 2.3 g (50.4%) of the title compound were obtained, and crystallized from dimethylformamide to obtain white crystals, m.p.: 280°-282° C. (under decomposition).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH:22]=O>CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Solvent: CO
Product: C[C@H](NCc1cc(Cl)cc(Cl)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
Borane-pyridine complex (130 μL, 1.21 mmol) was added to an methanol solution (4 mL) of an amine (3) (105 mg, 0.40 mmol) and 3,5-dichlorobenzaldehyde (95 mg, 0.52 mmol) at 40° C. and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol-10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (6) as a white solid (76 mg, yield 45%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.I[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[OH:1][CH2:2][C@H:3]1[N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3)CC2)nc1C

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one and (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (871 mg) described in Preparation Example 120 and by the reaction and treatment in the same manner as in Example 1, the title compound (348 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH4+:11].[OH-]>O>[NH2:11][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N)nc1

Procedure:
1-(6-Chloropyridin-3-yl)-ethanone (230 mg, 1.5 mmol), 1 mL 28% aq NH4OH, and catalytic CuSO4.5H2O were heated to 130° C. in a sealed tube for 5 h. The mixture was cooled, diluted with 20 mL water, and washed with 2×25 mL EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (163 mg, 80%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:11][S:10][C:9]([NH:12]C(=O)OC(C)(C)C)=[N:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[N:1]1([CH2:6][CH:7]2[CH2:11][S:10][C:9]([NH2:12])=[N:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1=NC(Cn2cncn2)CS1
Agent: Cl
Solvent: C1COCCO1
Product: NC1=NC(Cn2cncn2)CS1

Procedure:
a solution of 0.3 g of tert-butyl N-[(4RS)-4-(1,2,4-triazol-1-yl-methyl)-4,5-dihydro-2-thiazolyl]carbamate in 10 cm3 of 4N hydrochloric acid in dioxane is stirred at a temperature in the region of 20° C. for 34 hours. The reaction medium is filtered and then washed with 3 times 5 cm3 of diethyl ether and dried in a desiccator. 0.14 g of (4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is obtained in the form of a white foam [mass spectrum: EI m/z=184 MH+ m/z=183 M+ m/z=114 C4H6N2+ M/z=101 C3H5N2S+ base peak m/z=36 HCl DCI m/z=184 MH+].