Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:26]C(=O)C)([CH3:25])[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=O)C.O1CCCC1.CO.O.[OH-].[Li+]>O>[NH2:26][C@:6]([CH3:25])([CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(CCCCCc2ccccc2)o1)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@](N)(CO)CCc1ccc(CCCCCc2ccccc2)o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(5-phenylpentyl)furan-2-yl]butane (99.7 mg, 0.25 mmol) obtained in Example (6a) in a mixed solvent of tetrahydrofuran (0.5 ml) and methanol (0.5 ml) were added successively water (0.5 ml) and lithium hydroxide monohydrate (0.1037 g, 2.47 mmol), and the resulting mixture was stirred at 50° C. for 4 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (100:1) as the eluent to afford (2R)-2-amino-2-methyl-4-[5-(5-phenylpentyl)furan-2-yl]butan-1-ol (74.6 mg, yield: 95%).
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3]O.ClS(O)(=O)=O>C(#N)C>[CH2:5]([C:2]1([CH2:9][CH3:10])[CH2:3][NH:1]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(N)(CC)CO
Agent: O=S(=O)(O)Cl
Solvent: CC#N
Product: CCCCC1(CC)CN1
Temperature: 2.5 °C
Reaction time: 1.33 h
Yield: 73.1 %

Procedure:
Acetonitrile (150 ml) and the product from step (h) (20.0 g) were mixed under nitrogen, cooled to 2-3° C. and chlorosulphonic acid (16.0 g, Aldrich) was added dropwise keeping the temperature below 10° C. The coolant was removed and the slurry left to stir for 80 minutes at room temperature. The reaction was concentrated in vacuo and co-distilled with water (50 ml). 50% Aqueous sodium hydroxide (55.2 g) and water (50 ml) were added and the mixture was distilled at atmospheric pressure. The organic layer was collected from the distillate and dried with solid potassium hydroxide to give the desired product (12.8 g). 1H NMR consistent with proposed structure.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(COCCCCBr)cc1OC
Agent: Cl
Product: COc1ccc(COCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,4-dimethoxybenzyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,4-dimethoxybenzyloxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[H-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:27]([O:37][C@H:38]3[C@H:42]4[O:43][CH2:44][C@@H:45]([OH:46])[C@H:41]4[O:40][CH2:39]3)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.CCOC(C)=O.CCCCCC>CN(C=O)C>[CH2:1]([O:46][C@@H:45]1[CH2:44][O:43][C@@H:42]2[C@H:38]([O:37][C:27]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:10]4[C:11]([N:26]=3)=[N:12][C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][CH:19]=3)=[C:8]([Cl:7])[CH:9]=4)[CH2:39][O:40][C@H:41]12)[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Allyl iodide (130 μl, 1.422 mmol) and sodium hydride (16.0 mg, 0.400 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-3-ol (82.8 mg, 0.143 mmol) in DMF (1.4 ml). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc (75 ml), water (20 ml), and 2 N HCl (10 ml). The organic layer was washed with water (2×30 ml, brine was added to each wash to break an emulsion) and brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. Flash chromatography of the residue utilizing a 4 g silica RediSep Rf® column and employing a 0-40% EtOAc/hexane gradient followed by 40% EtOAc/hexane afforded the title compound as a pale yellow solid. LC-MS: calculated for C33H38ClN3O5Si 619.23 observed m/e: 620.32 (M+H)+ (Rt 1.43/2 min).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[C:6](=[O:19])[C:7]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)=[CH:8]1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: C1CCNC1
Product: Cn1nnnc1-c1cn(C)c2cc(N3CCCC3)ccc2c1=O

Procedure:
In a similar way to that described in Example 30, 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5 g) was boiled under reflux with pyrrolidine (50 ml) for 20 hours to give 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-7-pyrrolidino-4-quinolone, m.p. 267°-270° (from industrial methylated spirit:water 5:1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:18][C:19]1[CH:24]=[C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Product: Cc1cccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)c1

Procedure:
The title compound was prepared from the product of Example 105A and 3-methylphenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 326.0 (M+H)+, retention time 1.55 minutes.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([CH:38]2[CH2:40][CH2:39]2)=O)[C:31]=1[O:41][CH3:42]>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([CH:38]2[CH2:40][CH2:39]2)=[CH:2][O:3][CH3:4])[C:31]=1[O:41][CH3:42]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(Cl)ccnc1C(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C(c1nccc(Cl)c1OC)C1CC1
Temperature: -30 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (1.6 g, 4.7 mmol) was dissolved in THF (20 ml) and cooled to −30° C. 2.5 Molar n-BuLi in hexanes (1.89 ml, 4.7 mmol) was and the mixture stirred for 1 h. (4-chloro-3-methoxypyridin-2-yl)-(cyclopropyl)methanone (500 mg, 2.4 mmol) dissolved in THF (5 ml) was added slowly and stirred for 4 h. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and stirred overnight. 25 mL ethyl acetate was added and the layers partitioned. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to obtain crude product which was purified over silica gel using 0:1 to 3:7 ethyl acetate in heptane to obtain 4-chloro-2-(1-cyclopropyl-2-methoxyvinyl)-3-methoxy-pyridine as a clear oil (361 mg, 63%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:35]2[N:34]=[CH:33][C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:41])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)=[CH:37][CH:36]=2)[CH2:39][CH2:40]1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M204) (266 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (75 mg, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]=[C:18]=S)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH:26]([NH2:30])[CH2:25][CH2:24]2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([NH:30][CH:26]3[C:27]4[C:23](=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)[CH2:24][CH2:25]3)[O:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1N=C=S
Reactant: NC1CCc2cc(F)ccc21
Product: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Br)cc2CO1
Yield: 68.5 %

Procedure:
Prepared from (5-bromo-2-isothiocyanato-benzyloxy)-tert-butyl-dimethyl-silane (Example 32, step B) (4.0 g, 11.2 mmol) and rac-5-fluoro-indan-1-ylamine (CAS 148960-33-2) (1.69 mg, 11.2 mmol) according to the procedure described for Example 1. Obtained the title compound as a light brown oil (2.77 g, 69%), MS (ISP) m/e=361.1 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:43]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: O=C(O)c1cccnc1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)c2cccnc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and nicotinic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.01 minutes; C31H33ClN6O3 (573.10); mass spectrum: (M−H)−=572.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Br:16])[C:5]([F:8])([F:7])[F:6])=[N+]=[N-].C(O)=O.NN>[Ni].C(O)C>[Br:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH:4]([NH2:1])[C:5]([F:6])([F:7])[F:8]
Reactant: [N-]=[N+]=NC(c1ccc(F)cc1Br)C(F)(F)F
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O=CO
Product: NC(c1ccc(F)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Add Raney Nickel (1.58 g, 26.8 mmol) to a solution of 1-(1-azido-2,2,2-trifluoro-ethyl)-2-bromo-4-fluoro-benzene (0.8 g, 2.68 mmol), formic acid (1.24 g, 26.8 mmol), and hydrazine (0.86 g, 26.8 mmol) in 10 mL of ethanol. Stir the mixture at RT for 1 h and filter off the excess Nickel. Dilute the mother liquor with water and extract with chloroform. Dry the organic layer over sodium sulfate and concentrate to give the title compound as a brown oil (0.73 g, 100%). MS (ES) m/z 272/274 [M+1]+.
Reaction SMILES: B.C1COCC1.C([O:9][C:10](=O)[CH2:11][C:12]1(O)[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13]1=O)C.O1CCCC1.C(OCC)(=O)C>O>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[Cl:22])[NH:14][CH:13]=[C:12]2[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CC1(O)C(=O)Nc2cc(Cl)c(Cl)cc21
Agent: B
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 57 h
Yield: 60 %

Procedure:
A 1 M borane/THF solution (28.0 ml. 28.0 mmol) was added to a solution of the (5,6-dichloro-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic acid ethyl ester just prepared (2.13 g, 7.0 mmol), in abs. tetrahydrofuran (15 ml), in an ice bath in the course of 15 min. The reaction mixture was stirred at room temperature for 57 h and, for working up, was added to a mixture of ethyl acetate (50 ml) and water (50 ml), while stirring. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The organic phases were combined, dried and concentrated. The crude indole was obtained as a yellow oil (1.9 g) by this procedure. Purification by chromatography [silica gel G (80 g); ethyl acetate/cyclohexane 1:2 (2 l)] gave the desired 2-(5,6-dichloro-1H-indol-3-yl)ethanol (Ind-83) as a beige-coloured solid in a yield of 60% (0.96 g) (m.p. 65-67° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=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.C1(C)C=CC=CC=1>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:7][C:6]=2[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)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=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(-c2ccccc2)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 74.6 %

Procedure:
Methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (1.20 g), phenylboronic acid (0.30 g), tetrakis(triphenylphosphine)palladium (0.14 g), 2M aqueous sodium carbonate solution (3.7 mL), methanol (5 mL), and toluene (20 mL) were stirred with heating under reflux for 24 hrs under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (0.89 g, 74%) of methyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-112° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:11])=[S:10])=[CH:5][CH:4]=1.Br[CH2:15][CH:16]=O.Cl>C(O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:15]=[CH:16][N:11]=2)=[CH:5][CH:4]=1
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: O=CCBr
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2nccs2)cc1
Yield: 49.3 %

Procedure:
In a manner similar to Step B of Example 1, the reaction of 10.0 grams (0.0487 mole) of (4-trifluoromethylphenyl)thiocarboxamide, 125 ml of ethanol, 8.35 grams (0.0490 mole) of bromoacetaldehyde, and 2 ml of concentrated hydrochloric acid produced 5.5 grams of 2-(4-trifluoromethylphenyl)thiazole as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[NH:26][N:25]=[CH:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.BrC1C=CC(S(O[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]=[N+:47]=[N-:48])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[N:46]([CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][N:26]1[C:27](=[O:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[CH:24]=[N:25]1)=[N+:47]=[N-:48]
Reactant: COCOc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: [N-]=[N+]=NCCCCCCOS(=O)(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCOc1ccc(N2CCN(c3ccc(-n4cnn(CCCCCCN=[N+]=[N-])c4=O)cc3)CC2)cc1
Yield: 62 %

Procedure:
This compound was synthesized as a yellowish amorphous solid from 13 (114.4 mg, 0.30 mmol), 3p (130.4 mg, 0.36 mmol), and Cs2CO3 (146.6 mg, 0.45 mmol) in 62% yield by following general procedure 1.2: 1H NMR (400 MHz, CDCl3, δH) 7.61 (s, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.08-6.93 (m, 6H), 5.13 (s, 2H), 3.85 (t, J=7.1 Hz, 2H), 3.48 (s, 3H), 3.41-3.33 (m, 4H), 3.31-3.22 (m, 6H), 1.88-1.74 (m, 2H), 1.61 (dt, J=14.0, 7.0 Hz, 2H), 1.52-1.35 (m, 4H). ESI-MS: 507.3 (M+H+), 529.3 (M+Na+).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[CH3:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH:40][NH2:41])=O)[CH:33]=1>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:38]([C:34]3[CH:33]=[C:32]([CH3:31])[CH:37]=[CH:36][N:35]=3)=[N:40][N:41]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: Cc1ccnc(C(=O)NN)c1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Triethyloxonium tetrafluoroborate (314 mg, 1.654 mmol) was added under argon to a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(481 mg, 1.654 mmol) in Dichloromethane (DCM) (4 ml). The reaction was stirred at room temperature for 40 min (until mixture became clear). 4-methyl-2-pyridinecarbohydrazide (I28)(300 mg, 1.985 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and 1-butanol (4.00 ml) was added. The reaction mixture was stirred at reflux 1 h 20 min—after 40 min, the reaction mixture became completely clear. The reaction mixture was diluted with ethyl acetate (I50 mL) and then extracted water (2×25 mL), with sat. NaHCO3 (25 mL) and with brine (25 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP. The resulting oil was triturated in hexane (10 mL) and ether (10 mL) and dried at 60° C. under vacuum for 5 days to afford the desired product in 189.9 mg as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1
Yield: 100 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (200 mg), 4-indole-boronic acid (125 mg), sodium hydrogen carbonate (178 mg) and PdCl2(PPh3)2 (4 mg) in toluene (1.5 ml), ethanol (0.75 ml) and water (0.4 ml) were heated in a microwave at 120° C. for 45 min. Chloroform/water extraction and purification on silica gave 2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (257 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[CH2:37]([O:44][C@H:45]([CH3:49])[C:46](O)=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C1COCC1>[CH2:37]([O:44][C@H:45]([CH3:49])[C:46]([NH:15][NH:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)[C:10](=[O:28])[N:11]([CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[N:12]=1)=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)[C@@H](C)OCc2ccccc2)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (70 mg, 0.1367 mmol), prepared as described in Example 2B, (R)-2-(benzyloxy)propanoic acid (25 mg, 0.1367 mmol), EDAC (30 mg, 0.150 mmol), HOBT (20.3 mg, 0.150 mmol), THF (5 ml) and diisopropylethyl amine (19.4 mg, 0.150 mmol). The reaction was stirred at rt for 5 hr. The reaction was diluted with EtOAc (40 ml). The resulting organic solution was extracted with water (2×20 ml) and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography, (4 g silica gel) eluting with 20%-80% EtOAc/Hex to give product (R)-2-(benzyloxy)-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propanehydrazide as a beige solid (70 mg, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:12][N:8]1[CH2:7][CH2:6][C:5]2[N:4]=[CH:3][C:2]([NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]=2[CH2:9]1
Reactant: CN1CCc2ncc(N)cc2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCc2ncc(NC(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 53 %

Procedure:
3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine (314 mg, 1.9 mmol) was dissolved in dichloromethane (10 ml) and treated sequentially with triethylamine (214 mg; 2.1 mmol) and benzoyl chloride (297 mg; 2.1 mmol). The mixture was stirred at ambient temperature until tlc showed no starting material remaining. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate, water, saturated brine, dried (anhydrous magnesium sulphate) and evaporated to dryness under reduced pressure. Chromatography through silica gel, eluting with methanol in dichloromethane (0 to 50% methanol gradient), gave the title compound as an off-white foam (269 mg; 52%)