Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])=[CH:6][C:5]([CH3:16])=[CH:4][C:3]=1[N:17]1[N+:21]([O-])=[C:20]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]2=[N:18]1.[OH-].[Na+].O.NN.Cl>O.COCCOCCOC>[OH:1][C:2]1[C:7]([CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])=[CH:6][C:5]([CH3:16])=[CH:4][C:3]=1[N:17]1[N:18]=[C:19]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]2=[N:21]1
Reactant: Cc1cc(C(C)c2ccccc2)c(O)c(-n2nc3ccc(Cl)cc3[n+]2[O-])c1
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(C(C)c2ccccc2)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Temperature: 130 °C
Yield: 94.5 %

Procedure:
152 g (0.4 mol) of 2-(2-hydroxy-3-α-phenylethyl-5-methylphenyl)-6-chloro-benztriazole-1 oxide and 17.6 g (0.44 mol) of sodium hydroxide are introduced into 327 g of diethylene glycol dimethyl ether and the mixture is heated to 130° C, a little water distilling off azeotropically with the solvent. Exactly 12.0 g (0.24 mol) of hydrazine hydrate are passed in under the surface of the solution over the course of 11/2 hours while keeping the temperature between 133° and 135° C. In the course thereof, the water liberated is continuously removed by azeotropic distillation. After the addition is complete, the mixture is left to complete the reaction for about 1 hour at the same temperature and, as soon as the evolution of nitrogen stops, the resulting solution is cooled to 80° C and treated with 200 ml of cold water. About 53.7 g of 30% strength hydrochloric acid are then added dropwise at a regular rate until the mixture has a neutral reaction and it is cooled to about 40° C while stirring vigorously, whereupon the product crystallises out. The suspension is then diluted with 800 ml of water and filtered and the crude product is washed with a total of 300 ml of hot water. After drying in vacuo at 60°-70° C, 137.5 g of 2-(2-hydroxy-3-α-phenylethyl-5-methylphenyl)-5-chloro-benztriazole of 97% purity are obtained, which corresponds to a yield of 91.5% of theory. The melting point is 113°-115° C (the pure product melts between 115° and 119° C).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](SC)[C:6]([F:11])=[CH:5][N:4]=1.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:13][NH2:14])[C:6]([F:11])=[CH:5][N:4]=1
Reactant: CSc1ncc(F)c(SC)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1ncc(F)c(NN)n1
Temperature: 0 °C
Yield: 86 %

Procedure:
A 1 liter (L) flask equipped with a condensor and thermometer was charged with 80g (0.42 moles) of 2,4-bis(methylthio)-5-fluoropyrimidine, 200 mL of ethanol and 105g (2.1 moles) of hydrazine hydrate. The reaction mixture was poured onto 350 mL of ice-water. The solid product was isolated by filtration. After washing with water, the product was dried under vacuum at 60° C. to give 62.8g (86 percent yield) of 2-methylthio-4-hydrazino-5-fluoropyrimidine having a melt point of 146°-147° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].Cl.O.[N:46]1([CH2:52][CH:53]=O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C([BH3-])#N>CO>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:53][CH2:52][N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[CH2:24]2)[CH:17]=[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCNC2)cn1
Reactant: O=CCN1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A vial was charged with ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Example 239, 700 mg, 1.14 mmol), morpholin-4-yl-acetaldehyde monohydrate hydrochloride (260 mg, 1.39 mmol) and methanol (10 mL). MP-cyanoborohydride beads (730 mg, 1.71 mmol) were added and the resulting mixture was allowed to stir at room temperature overnight. The reaction went to completion based on LC. The mixture was filtered and the beads were washed with methanol. The filtrate was concentrated under reduced pressure and purified by Analogix SF15-24 g column eluting with dichloromethane/methanol system to give a light yellow solid (310 mg, 37.4%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([Cl:16])[CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.B>C1COCC1>[C:17]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][OH:12])=[C:9]([Cl:16])[CH:8]=2)[N:5]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)c(Cl)c2)n1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(Cl)c2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)-2-chlorobenzoic acid (1.15 g, 75% purity, 2.9 mmol) in THF (6.0 mL) at 0° C. under N2 was added a solution of borane in THF (1.0 M, 11.7 mL, 11.7 mmol) over 5 min and the reaction mixture warmed to RT for 6 hr. An additional aliquot of the borane solution (3.0 mL, 3.0 mmol) was added and the reaction mixture maintained at RT for a further 18 hr, then quenched by the addition of MeOH (30 mL) and after 10 min at RT was evaporated in vacuo. The residue was partitioned between DCM (20 mL) and brine (10 mL). The aq layer was separated and was extracted with DCM (10 mL) and the combined organic layers were dried and evaporated in vacuo to afford 3-(tert-butyl)-1-(3-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-5-amine as a dark orange oil (1.15 g, 70% purity, 98%); Rt 3.92 min (Method 1 basic); m/z 280 (M+H)+, (ES+). This material was used in the subsequent step without further purification
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].I[C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.O.C(Cl)Cl>C(NCC)C.[Cu]I.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>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:1][C:2]#[C:3][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1
Reactant: C#CCOC1CCCCO1
Reactant: Nc1ccc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Solvent: ClCCl
Product: Nc1ccc(C#CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
2-(2-Propynyloxy)tetrahydro-2H-pyran (360 mg), 5-iodo-2-pyridinylamine (440 mg), CuI (140 mg) and dichlorobis(triphenylphosphine)palladium (60 mg) are dissolved in diethylamine (10 mL). After the mixture is stirred for 1 h at room temperature, water (40 mL) and CH2Cl2 (80 mL) are added. The organic layer is separated, dried (MgSO4) and concentrated. The resulting residue is purified on a silica gel plate (CH2Cl2/methanol, 9/1) to give 230 mg (50%) of the title compound as an oil which slowly solidifies. MS (ESI+) m/z 233 (M+H)+. 1H NMR (CDCl3) δ 8.10, 7.60, 6.65, 5.90, 4.86, 4.48, 3.90, 3.5-3.6, 1.55-1.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2-methylpyridine (1.0 eq.) in chloroform (0.38 M) was added 77% meta-chloroperbenzoic acid (mCPBA) (4.0 eq.) and heated at 60° C. for 20 hours. After cooling to room temperature, Ca(OH)2 (5.3 eq.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 3:1 CHCl3/methanol. The filtrate was concentrated en vacuo to give a solid, which was stirred in 30% ethyl acetate in hexane and filtered to give the desired N-oxide. The filtrate was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give more of the desired N-oxide. The two batches were combined and carried onto the next step.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:18]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35](OC)=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:46][NH2:47]>CN(C=O)C>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C@H:2]([C:18]([NH:20][C@H:21]([C:27]([NH:29][C@H:30]([C:35]([NH:46][NH2:47])=[O:36])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[CH2:22][CH2:23][C:24](=[O:26])[NH2:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC
Reactant: NN
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 8 h
Yield: 88.5 %

Procedure:
The tripeptide methyl ester (XIII) (1 g, 1.6 mmol) was suspended in DMF (5 ml), hydrazine (0.8 g, 0.78 ml, 16 mmol) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the residue solidified using MeOH/EtOAc to give (XIV) (0.9 g, 90%). T.l.c. RfA3 =0.70 This was used immediately in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24].[H-].[Na+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=[CH:10][CH:11]=1)[C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH3:2]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1cccc(-c2cccc(Cl)c2Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1cccc(-c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2′,3′-dichloro-[1,1′-biphenyl]-3-acetic acid ethyl ester (i.e. the product of Step A, 0.45 g, 1.45 mmol) and diethyl carbonate (5 mL) was added sodium hydride (60% dispersion in oil, 0.23 g, 5.8 mmol). The reaction mixture was stirred overnight at room temperature, and then quenched with saturated aqueous ammonium chloride solution. The reaction mixture was then extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (0.50 g).
Reaction SMILES: [C:1]1([C:7](=NN)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)=[N+]=[N-])C=CC=CC=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>[Hg]=O>[CH2:36]([O:35][C:31]([CH:32]1[CH2:33][C:7]1([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:34])[CH3:37]
Reactant: C=CC(=O)OCC
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: O=[Hg]
Agent: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 95.9 %

Procedure:
Diphenylketone hydrazone (3.92 g, 20 mmol) was mixed with yellow mercury oxide (4.33 g, 20 mmol) in 40 mL petroleum. The mixture was stirred at the temperature less than 20° C. for 16 hours. The deep red solution of diphenyl diazomethane in petroleum was added into ethyl acrylate (6.0 g, 60 mmol) at 50° C. in ten minutes. When the red colour fade off the solvent and excess of ethyl acrylate were removed under reduced pressure and the crude product obtained was further purified over silica chromatography to furnish 2,2-diphenylcyclopropanyl carboxylate ethyl ester 5.11 g (96% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): 7.36-7.17 (10H, m), 4.00-3.83 (2H, m), 2.54 (1H, dd, J=8.3, 6.0 Hz), 2.17 (1H, dd, J=1H, dd, 6.0, 4.8 Hz), 1.59 (1H, dd, J=8.3, 4.8 Hz), 1.01 (3H, t, J=7.1 Hz).
Reaction SMILES: CO[CH:3]([N:6]([CH3:8])[CH3:7])OC.[Br:9][C:10]1[S:14][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:12][CH:11]=1.[Cl-].[Na+]>CN(C=O)C>[CH3:7][N:6]([CH:3]=[N:18][S:15]([C:13]1[S:14][C:10]([Br:9])=[CH:11][CH:12]=1)(=[O:17])=[O:16])[CH3:8]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1ccc(Br)s1
Yield: 114.1 %

Procedure:
Add dimethoxymethyl-dimethyl-amine (1.05 mL, 7.66 mmol) to a solution-of 5-bromo-thiophene-2-sulfonic acid amide (1.8 g, 7.43 mmol) in DMF (3 mL) at r.t. for 16 h. Pour reaction mixture into saturated sodium chloride, extract with ethylacetate. Wash combined organic layers with water, dry over sodium sulfate and remove solvent to obtain 2.52 g product. MS (m/e): 297.0/299.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccncc1
Product: O=C(Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1)c1ccncc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and isonicotinic acid as starting materials, MS (LC/MS): 380.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[H-].[Na+].Cl[C:14]1[CH:15]=[C:16]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][O:1][C:14]1[CH:15]=[C:16]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1)#[N:7]
Reactant: N#Cc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cccc(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 3-(hydroxymethyl)benzonitrile, sodium hydride and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:30])[CH3:29]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:30]=[C:28]([CH3:29])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.29 mmol) of the compound from Example 130A and 33 mg (0.43 mmol) of N′-hydroxyacetamidine were reacted according to the General Method 2. Yield: 68 mg (61% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([NH:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])=[CH:21][CH:22]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(CNc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 99.2 %

Procedure:
A mixture of 6.14 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate, 130 ml of 95% ethanol and 52 ml of 1 N aqueous solution of sodium hydroxide is stirred at 70° C. for 50 minutes. After concentrating the reaction mixture under reduced pressure, the residue is dissolved in water and the solution is washed with ether five times. To the aqueous solution is added 55 ml of 1 N hydrochloric acid with cooling, and the precipitated crystals are extracted twice with ether. The extract is washed with water twice, then dried over magnesium sulfate and thereafter the solvent is distilled off to give 5.6 g of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid, colorless crystals, mp 155° to 158° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[O:10])[CH:5]=[C:4]([CH3:22])[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:22])[N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:19][CH2:18]2)[CH3:21])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CNC1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)C(=O)Cc3ccc(Cl)c(Cl)c3)CC2)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) mixture of 1-(2,6-dimethyl-pyridin-4-yl)-3-[2-(4-methylamino-piperidin-1-yl)-ethyl]-urea (Example E1., 0.3 mmol) and TEA (0.5 mL, 0.35 mmol) in CH2Cl2 (2 mL) is added a solution of (3,4-dichloro-phenyl)-acetyl chloride (67.0 mg, 0.3 mmol) in CH2Cl2 (1 mL). The mixture is stirred at r.t. for 15 h and evaporated. the residue is purified by HPLC to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]2[O:32][C:22]3=[C:23]4[C:28](=[CH:29][CH:30]=[C:21]3[O:20][CH2:19]2)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]4)=[CH:3]1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([CH2:13][CH2:14][CH2:15][N:16]([CH3:35])[CH2:17][CH:18]2[O:32][C:22]3=[C:23]4[C:28](=[CH:29][CH:30]=[C:21]3[O:20][CH2:19]2)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]4)=[CH:3]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCc1cn(C)c2ccc(C#N)cc12)O3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN(C)CCCc1cn(C)c2ccc(C#N)cc12)O3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-methyl-3-{3-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-proyl}-1H-indole-5-carbonitrile (0.1 g, 0.23 mmol) and formaldehyde (37 wt. % in water, 0.19 g, 2.3 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.026 g, 0.41 mmol) and acetic acid (0.027 mL, 0.46 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 2 hours, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 165° C.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:8].Cl.[NH2:10][C:11]1C=CC=[CH:13][CH:12]=1.N([O-])=O.[Na+].C(#N)C=C>O.CO>[Cl:8][CH:12]([CH2:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]#[N:10]
Reactant: Nc1ccccc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C=CC#N
Product: N#CC(Cl)Cc1ccccc1
Yield: 88 %

Procedure:
55.8 g (0.6 mol) of aniline and 200 ml of a 25% hydrochloric acid aqueous solution were mixed to obtain a suspension of aniline hydrochloride. While cooling this solution to a temperature of from 0° to 10° C. from outside and stirring it, a solution prepared by dissolving 42.5 g (0.615 mol) of sodium nitrite in 85 ml of distilled water, was dropwise added over a period of about 4 hours. After the completion of the dropwise addition, the reaction mixture was stirred for about 1 hour at a temperature of from 0° to 10° C. To this solution, 200 ml of methanol and 95.4 g (1.8 mols) of acrylonitrile were added, and while stirring the mixture under cooling, 5 g of cuprous oxide powder was gradually added. The reaction mixture was stirred at a temperature of from 10° to 20° C. for 4 hours, and then methanol and unreacted acrylonitrile were distilled off by distillation. The residual solution was separated into an aqueous phase and an organic phase. The organic phase was subjected to distillation under reduced pressure, whereby 87 g (yield: 88%) of α-chloro-β-phenylpropionitrile was obtained. (b.p.: 105°-110° C./4 mmHg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18](C2CCCCO2)[N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccnn2C2CCCCO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To a solution of the 5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.15 g, 3.52 mmol) prepared in Example 148a in dichloromethane (10 mL), trifluoroacetic acid (5.0 mL) was added at room temperature, and the reaction solution was stirred for 12 hours. The reaction solution was concentrated, and a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the residue, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed with saturated saline (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:1) to yield the title compound (840 mg, 98%) as a pale yellow oil.