Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: COc1cc(C(=O)C2CC2)c(F)cn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1cc(OC)ncc1F)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.76 g) in THF (100 mL) was added ethyl diethylphosphonoacetate (15.2 mL) at 0° C., and the mixture was stirred at 0° C. for 5 min. To the obtained colorless solution was added cyclopropyl(5-fluoro-2-methoxypyridin-4-yl)methanone (entire amount) obtained in Example 42, step B, at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([O:15]C)=[CH:6][CH:5]=2.C1(CN2C3C(=CC=CC=3)C(CC(N)=O)=C2)C=CC=CC=1.B(Br)(Br)[Br:45].C(Cl)Cl.Cl>C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[C:8]([Br:45])[C:7]([OH:15])=[CH:6][CH:5]=2.[Br:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([OH:15])=[CH:6][CH:5]=2
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(Br)n2Cc1ccccc1
Agent: Cl
Agent: NC(=O)Cc1cn(Cc2ccccc2)c2ccccc12
Solvent: ClCCl
Product: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)c(Br)c12
Product: NC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(O)cc12
Reaction time: 2.5 h

Procedure:
A solution of 600 mg (1.6 mmol) of 2-bromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (lot was contaminated with 2,4-dibromo-5-methoxy-]-(phenylmethyl)-1H-indole-3-acetamide) and 10 mL of 1M BBr3/CH2Cl2 in 100 mL of CH2Cl2 was stirred for 2.5 hours, 100 mL of 1N HCl added, stirred well, and the CH2Cl2 layer separated. After washing and drying (Na2SO4), the solvent was removed at reduced pressure. The residue was chromatographed on silica and eluted with a gradient (1% MeOH/CH2Cl2→4% MeOH/CH2Cl2) to give in the early fraction 2,4-dibromo-5-hydroxyl-1-(phenylmethyl)-1H-indole-3-acetamide (115 mg) and in the later fractions 2-bromo-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (115 mg). The material from the later fractions (100 mg, 0.28 mmol) was dissolved in 20 mL of DMSO, 20 mg of 60% NaH/mineral was added, and after 10 minutes, 0.1 mL of ethyl 4-bromobutyrate was added. After heating for 1.25 hours at 85° C., the mixture was diluted with water, extracted with EtOAc, and the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with 1% MeOH/CH2Cl2→3% MeOH/CH2Cl2) to give 80 mg of 4-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester as an oil. This material was dissolved in 20 mL of EtOH, 1 mL of 2N NaOH added, and the mixture stirred for 19 hours. After acidifying with 1N HCl, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was crystallized from EtOH/ether to give 80 mg of 4-[[3-(2-amino-2-oxoethyl)-2-bromo-1-(phenylmethyl)-1H-indol-5-yl]oxy]-butanoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH3:19][N:20]([CH3:24])[C:21]([N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:22]
Reactant: CN(C)CCNc1nccs1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)CCN(C(=O)N(C)C)c1nccs1

Procedure:
Following the procedure of Example 1C using 18.2 g. (0.1065 moles) of N,N-dimethyl-N'-(2-thiazolyl)-1,2-ethane diamine, 12.1 g. (0.120 moles) of triethylamine, 12.5 g. (0.116 moles) of dimethylcarbamoyl chloride and 135 ml. of dry benzene, there is obtained 20.1 g. of N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-thiazolyl)urea as an oil which is distilled at 108°-110° C., at 0.02 mm. of Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:18](O)(=O)C.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCl.CO>[CH3:18][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(C(N)=O)cc2)CC1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4-piperidin-4-ylbenzamide (200 mg, 1.00 mmol), 37% aqueous formaldehyde (162 μL, 2.00 mmol), and acetic acid (86 uL, 1.5 mmol) in a mixture of dichloromethane and methanol (2:1, 6 mL) was added sodium triacetoxylborohydride (318 mg, 1.5 mmol) in portions over fifteen minutes and stirring was continued for 2 hr at room temperature. The reaction was then quenched with water and adjusted to pH 9 with 2N aqueous sodium hydroxide then extracted with dichloromethane (2×50 ml). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated to give 4-(1-methylpiperidin-4-yl)benzamide (190 mg, 87%). MS (EI) for C13H18N2O: 218 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30]>>[CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][S:29]([C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=3)(=[O:31])=[O:30])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc(Cc2ccccc2)c(-c2ccc(-c3ccc(O)cc3)cc2)c1C
Product: Cc1sc(Cc2ccccc2)c(-c2ccc(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)cc3)cc2)c1C

Procedure:
The title compound was prepared from 4′-(2-benzyl-4,5-dimethyl-thiophen-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 173-175° C.; MS m/e 570 (M−H)+;
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:2]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ncccn1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cn2cccnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
2-Bromo-2′-nitroacetophenone (5.0 g, 20.4 mmol) and 2-aminopyrimidine (1.94 g, 20.4 mmol) were dissolved in acetone (50 ml) and brought to reflux. After 60 minutes a light white precipitate developed. Refluxing was continued for 5.5 hours and cooled to room temperature. The volume was reduced 1 by evaporation and the intermediate solids were collected by filtration, washed with acetone (20 ml) and air dried (2.84 g of intermediate). A second crop was collected by concentration of the combined mother liquors, and refluxing the residue in fresh acetone (20 ml) for 1.5 hours. Upon cooling, and reducing the volume by ½ by evaporation, 3.11 g of solids were collected. The combined solid intermediate (5.95 g) was dissolved in MeOH (70 ml) with 5 drops of conc. HBr and refluxed for 2 hours. After cooling the volume was reduced by ½, water (40 ml) was added solution was made basic (pH=10) with 1N NaOH. Roto-evaporation to remove methanol resulted in the product crystallizing. The product was filtered, washed with water and air dried to obtain 5.03g of the desired product. (MS, M++H=241.0)
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(O)C.CN(C)C=O>[C:17]([C:16]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)(=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1O
Reactant: O=C(CBr)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2ccccc2o1
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To a solution of sodium ethoxide prepared from 28 g sodium metal and 500 ml absolute ethanol was added 122 g (1 mole) salicylaldehyde and 200 ml dimethylformamide. The mixture was heated to 80° C. Then 200 g (1 mole) alpha-bromoacetophenone was added in small portions. The mixture was stirred at reflux for 1.5 hours after which the ethanol was distilled. The residue was cooled and partitioned between 750 ml water and 750 ml ethyl acetate. The organic layer was washed twice with 400 ml portions of 1N sodium hydroxide, water (2×300 ml), dried (Na2SO4), concentrated to one-third volume, filtered to remove precipitated product which was washed with ethyl ether to yield 75.8 g of 2-benzoylbenzo(b)furan as pink crystals, m.p. 88°-90° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:38]=[C:26]1[CH2:27][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[NH:21]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: Cc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1

Procedure:
Prepared from (3-amino-4′-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G16) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a white solid (76 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[N:28]1([S:34]([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([S:34]([C:37]2[CH:38]=[C:39]([NH:43][C:25]([C:24]3[CH:23]=[N:22][N:15]4[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]([C:4]5[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=5)=[N:13][C:14]=34)=[O:27])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 614.4 [(M+H)+]; mp 272° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Reactant: ClCCN1CCCCC1
Product: CN1C(=O)c2c(c3ccc(Cl)cc3n2CCN2CCCCC2)Oc2ccccc21

Procedure:
In the same way as described in example 19, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepin-6(5H)-one was alkylated with piperidinoethyl chloride. The crude solid base was recrystallized from acetonitrile, mp. 160°-2°.
Reaction SMILES: C(CC(=O)C)(=[O:3])C.[C:8](#[N:12])[CH2:9][C:10]#[N:11].N1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[C:10]([C:9]1[C:8](=[O:3])[NH:12][C:17]([CH3:18])=[CH:16][C:15]=1[CH3:14])#[N:11]
Reactant: CC(=O)CC(C)=O
Reactant: N#CCC#N
Reactant: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C#N)c(=O)[nH]1

Procedure:
Bergel et al [British Pat. No. 553,097, accepted May 7, 1943] shows the reaction of acetylacetone with malononitrile in ethanol in the presence of piperidine to produce 3-cyano-4,6-dimethyl-2(1H)-pyridinone (named as its 5-cyano-2,4-dimethyl-6-hydroxypyridine tautomer).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:27]1([O:33][CH2:34][CH2:35][CH2:36][Br:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Br-:37].[OH:10][C:9]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:36][CH2:35][CH2:34][O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: COc1cccc(C(O)(c2cccc(OC)c2)C23CCN(CC2)CC3)c1
Reactant: BrCCCOc1ccccc1
Solvent: CC#N
Product: COc1cccc(C(O)(c2cccc(OC)c2)C23CC[N+](CCCOc4ccccc4)(CC2)CC3)c1
Product: [Br-]
Yield: 33.2 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl{bis[3-(methyloxy)phenyl]}methanol (0.0506 g, 0.143 mmol) and 3-bromopropyl phenyl ether (0.0338 mL, 0.214 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.027 g, 33.2%). EI-MS m/z 488(M+) Rt (2.02 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>[Cu]=O.O.C1(C)C(C)=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]2[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
93 g of aniline, 3.8 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, 2 g of copper(II)oxide and 40 ml of xylene are heated together to 150° C. for 20 minutes in a water separator. 157.5 g of 4-nitrochlorobenzene, 93 g of aniline and 76 g of calcined sodium carbonate (light) are then added. After 12 hours at 193°-196° C., 10 ml of water have collected in the water separator. The weight ratio of nitrobenzene:4-nitrochlorobenzene:4-nitrodiphenylamine in the reaction mixture is 1.5:2.0:96.5. The reaction mixture is cooled to 95° C. and filtered, and the filter cake is washed with 100 ml of hot xylene. Water is added to the filtrate, and unreacted 4-nitrochlorobenzene and aniline are expelled with steam, the 4-nitrodiphenylamine being obtained as granules. It is isolated by filtration, washed with hot water and dried: 210 g of 4-nitrodiphenylamine, purity (HPLC) 91.3%, yield 89.6 % of theory, relative to p-nitrochlorobenzene employed.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Clc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(Cl)cccc21
Yield: 66 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 4-chloro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 247 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:9][C:10](=[N:13][OH:14])[CH2:11][CH3:12]>ClCCCl>[C:1]([NH:6][C:7]([O:14][N:13]=[C:10]([CH2:11][CH3:12])[CH3:9])=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CCC(C)=NO
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)ON=C(C)CC
Yield: 95.9 %

Procedure:
To a solution of methacryloyl isocyanate (2.22 g; 20 mmol) in 1,2-dichloroethane (7.7 g), methylethylketone oxime (1.74 g; 20 mmol) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, the solvent was removed under reduced pressure to give 2-methacryloylcarbamoyloxyiminobutane (3.80 g) as a pale yellow liquid. Viscosity, 4600 cp.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:15]Br>O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:15]
Reactant: Nc1ccncc1C(=O)O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cncc1C(=O)O
Temperature: 75 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
A sealed tube was charged with 4-aminonicotinic acid 45 (8.00 g, 57.9 mmol), acetic acid (75 mL) and water (75 mL). The reaction was heated at 75° C. and stirred vigorously until homogeneous. After cooling to 50° C., bromine (10.0 mL, 195 mmol) was added and stirring continued for 16 h. Upon cooling to 0° C., the resulting orange precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 46 (10.5 g, 84% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH:19][C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccccc1-c1nnc(C2(N)CCCC2)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1nnc(C2(NC(=O)Nc3ccccc3)CCCC2)n1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-[4-Methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentanamine (263 mg) was dissolved in chloroform (5 ml) and then diisopropylethylamine (1.7 ml) and phenyl isocyanate (0.43 ml) were added thereto, followed by stirring at room temperature for 90 minutes. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:19) and the resulting solid washed with ethyl acetate to obtain 68 mg of 1-{1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentyl}-3-phenylurea (white solid).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3C=CC(C4C=CC=CC=4)=[CH:18][C:13]=3[CH2:12][N:11](C(C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:10][CH2:9]2)[N:4]=[CH:3]1.Cl.N1C=C(CN2C3C=CC=CC=3CN(C([C:57]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64]C=4)[CH:60]=[CH:59][CH:58]=3)=O)CC2)N=C1.[CH:67]([C:69]1[N:70]=[CH:71][NH:72][CH:73]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[ClH:1].[ClH:1].[NH:72]1[CH:73]=[C:69]([CH2:67][N:11]2[C:12]3[CH:64]=[CH:63][C:62]([C:61]4[CH:66]=[CH:57][CH:58]=[CH:59][CH:60]=4)=[CH:18][C:13]=3[CH2:14][N:8]([CH2:7][C:5]3[N:4]=[CH:3][NH:2][CH:6]=3)[CH2:9][CH2:10]2)[N:70]=[CH:71]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccc3)cc2C1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(-c2ccc3c(c2)CN(Cc2c[nH]cn2)CCN3Cc2c[nH]cn2)cc1

Procedure:
Example 45 was prepared as an off white solid from Compound B of Example 12 as described for Compound D of Example 1, using methylene chloride as solvent, 4.3 equivalents of 4-formylimidazole, 4.3 equivalents of sodium triacetoxyborohydride and with stirring for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[O:18]1[C:20]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19]1>CCO.O>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][CH2:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:19][C:20]2([OH:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:17]
Reactant: Nc1cccc(C#CCNC(=O)C(F)(F)F)c1
Reactant: C1CCC2(CC1)CO2
Solvent: CCO
Solvent: O
Product: O=C(NCC#Cc1cccc(NCC2(O)CCCCC2)c1)C(F)(F)F

Procedure:
A mixture of N-(3-(3-aminophenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide (0.75 g, 3.09 mmol) and 1-oxaspiro[2.5]octane (1.2 g, 9.2 mmol) in EtOH:H2O (9:1) was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)prop-2-ynyl)acetamide as an off white solid. Yield (0.48 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.53-6.51 (m, 2H), 6.39 (d, J=7.6 Hz, 1H), 5.28 (t, J=5.6 Hz, 1H), 4.18 (s, 1H), 4.01 (s, 2H), 2.88 (d, J=5.6 Hz, 2H), 1.60-1.47 (m, 4H), 1.39-1.34 (m, 4H), 1.22-1.14 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[CH:39]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(F)c1)N1CCN(C2CCCC2)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (46%).