Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CC([N:6]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[NH:7][C:8]([NH2:10])=[O:9])=O)#N.[OH2:19].[OH-].[Na+]>C(O)C>[NH2:6][C:11]1[N:7]([NH:6][C:11]2[C:12]([CH3:18])=[CH:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:8](=[O:9])[NH:10][C:13](=[O:19])[CH:12]=1
Reactant: Cc1cccc(C)c1N(NC(N)=O)C(=O)CC#N
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Nn1c(N)cc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
One mole of the above phenylsemicarbazide is added to 400 ml of water, followed by the addition of 200 ml of ethanol. This mixture is heated to 85° and 165 ml of 10% sodium hydroxide is added. After 30 minutes the mixture is acidified to pH 5, cooled to RT, filtered and recrystallized in acetone/water, yielding 6-amino-1-(2,6-dimethylanilino)-2,4-pyrimidinedione.
Reaction SMILES: CC1CCCN(C)C1(C)C.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.CN(C)[CH:23]=[O:24]>O1CCCC1.C([Li])CCC>[Cl:11][C:12]1[CH:20]=[C:19]([CH:23]=[O:24])[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)ncc1C(=O)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 53.19 %

Procedure:
To a stirred solution of tetramethylpiperidine (6.89 mL, 40.8 mM) in dry tetrahydrofuran (20 mL), n-butyl lithium (36.5 mL, 1.12 mL, 40.8 mM) was added drop wise at −78° C. for 15 min. The reaction mixture was stirred at −78° C. for 30 min and at −50° C. for 30 min. 6-Chloro nicotinic acid (1.6 g, 10.2 mM) dissolved in dry tetrahydrofuran (10 mL) was added dropwise to the above reaction mixture for 15 min at −78° C. The reaction mixture was stirred at −78° C. for 30 min and at −50° C. for 30 min. Dry dimethyl formamide (5 mL) was added dropwise at −78° C. for 5 min. The reaction mixture was stirred at −78° C. for 30 min and at −50° C. for 30 min. After the completion of the reaction, reaction mixture was quenched with 2N hydrochloric (30 mL) extracted with ethyl acetate (2×150 mL). Organic layer dried over anhydrous MgSO4, then concentrated. The concentrate was subjected to column chromatography, and the product was eluted with 15% ethyl acetate in petroleum ether to get 1.01 g (53.19%) of the title compound. MS (APCI): 186 (M+H+) for C7H4ClNO3; NMR CD3OD): δ 6.18 (s, 1H), δ 7.75 (s, 1H), δ 8.74 (s, 1H).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])C=2OC)[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)[C:28]([OH:30])=O.C[CH2:34][O:35]CC>>[CH3:22][O:21][C:17]1[C:18]([O:35][CH3:34])=[CH:19][CH:20]=[CH:15][C:14]=1[C:11]1([CH:28]=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOCC
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Product: COc1cccc(C2(C=O)CCNCC2)c1OC
Reaction time: 0.75 h

Procedure:
4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50 mL, 650 mmol) and stirred for 45 minutes. The entire solution was poured into ether (900 mL) and allowed to stand overnight. Filtration yielded 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trieluoroacetate as fine white needles, m.p. 123° C. Anal. Calcd for C14H19NO3.CF3CO2H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[NH4+].[Ce].[C:7]([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@@H:25]3[C@H:16]([C@H:17]4[C@@:21]([CH2:23][CH2:24]3)([CH3:22])[C@@H:20]([O:29][C:30](=[O:32])[CH3:31])[CH2:19][CH2:18]4)[C@H:15]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][S:42]([CH2:45][CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])(=[O:44])=[O:43])[CH2:14][C:13]=2[CH:12]=1)(=[O:9])[CH3:8].C(O)(=[O:57])C>>[C:7]([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@:25]3([OH:57])[C@H:16]([C@H:17]4[C@@:21]([CH2:23][C@@H:24]3[O:2][N+:1]([O-:4])=[O:3])([CH3:22])[C@@H:20]([O:29][C:30](=[O:32])[CH3:31])[CH2:19][CH2:18]4)[C@H:15]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][S:42]([CH2:45][CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:50])([F:51])[F:52])(=[O:43])=[O:44])[CH2:14][C:13]=2[CH:12]=1)(=[O:9])[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1ccc2c(c1)C[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: [Ce]
Agent: [NH4+]
Product: CC(=O)Oc1ccc2c(c1)C[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@H]1[C@@H]3CC[C@H](OC(C)=O)[C@@]3(C)C[C@H](O[N+](=O)[O-])[C@]21O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.6 g of cerium ammonium nitrate is added to a solution of 3.0 g of 3,17β-diacetyloxy-7α-(9-[4,4,5,5,5-pentafluoropentanesulfonyl]-nonyl)-estra-1,3,5(10)-triene in 50 ml of aqueous acetic acid (90%), and it is stirred for 4 hours at room temperature.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH2:36][C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.C(C1C=C(N=C=O)C=CC=1)#N>>[C:37]([C:7]1[CH:6]=[C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:3][CH:2]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: N#Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)ccc2C1=O

Procedure:
The compound of example 254 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-cyanophenyl isocyanate. The compound of example 254 was used directly without isolation for the preparation of compound of example 255.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[S:25][C:15]=2[N:16]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cnccn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:4]4[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@@H](C)O[C@@H](C)C3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
Following the same procedure in Example 3, Step A, using (2R,6S)-2,6-dimethylmorpholine (34.6 mg, 0.30 mmol), diisopropylethylamine (69.7 μL, 51.7 mg, 0.40 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (65.9 mg, 0.20 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (91.3 mg, 0.24 mmol). The mixture was stirred overnight at room temperature, added H2O (50 mL), extracted with EtOAc (3×50 mL). The desired title compound was purified by MPLC (hex/EtOAc 1:1 as eluent on silica gel) to give 75.7 mg (89%) of a white solid. 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.52 Hz, 3 H), 1.04 (m, 3 H), 1.28 (m, 8 H), 1.66 (m, 2 H), 1.69 (s, 6 H), 1.71 (m, 1 H), 1.79 (m, 2 H), 2.04 (q, J=7.42 Hz, 2 H), 2.13 (m, 1 H), 2.63 (m, 1 H), 2.92 (m, 1 H), 3.58 (m, 3 H), 4.50 (d, J=7.62 Hz, 2H), 4.55 (m, 1 H), 7.65 (dd, J=8.69, 1.46 Hz, 1 H), 7.81 (d, J=0.78 Hz, 1 H), 8.01 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)+=426.2. Anal. Calcd for C26H39N3O2+1.60 TFA+0.30 H2O (613.46): C, 57.17; H, 6.77; N, 6.85. Found: C, 57.18; H, 6.69; N, 6.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([C:32]([O:34]CC)=[O:33])=[N:26][CH:27]=2.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[C:32]([C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[CH:27][N:26]=1)([OH:34])=[O:33]
Reactant: CCOC(=O)c1ncc2[nH]c(=O)n(-c3cc(OCc4c(OC)ccc(F)c4F)c(OC)cc3Cl)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3cnc(C(=O)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-cyano-7,9-dihydro-8H-purin-8-one (0.12 g) was added hydrochloric acid (20% ethanol solution, 3 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diethyl ether, and dried under reduced pressure. The obtained crystals were purified by column chromatography on silica gel (eluent: ethyl acetate) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-ethoxycarbonyl-7,9-dihydro-8H-purin-8-one (93 mg). To the obtained 9-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenyl]-2-ethoxycarbonyl-7,9-dihydro-8H-purin-8-one (50 mg) were added tetrahydrofuran (4 mL), methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (40 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and the solvent was removed under reduced pressure. The residual solids were suspended in diethyl ether, and collected by filtration. The collected solids were washed with water and diethyl ether, and dried under reduced pressure to give the title compound (22 mg).
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].CN(C)CCCNC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1>>[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: CN(C)CCCCN
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 93 mg, 0.19 mmol) and N,N-dimethyl-butane-1,4-diamine (1.0 mL) using a similar method to that used in Example 28 (47 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[N:4][C:5](Cl)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[CH3:32][O-:33].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[N:4][C:5]([O:33][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1
Reactant: O=C(c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl)N1CCC(N2CCCC2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(Cl)cc1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for the preparation of example 8, [3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 21) was reacted with sodium methoxide in methanol at 50° C. to give the title compound as light yellow oil. MS: 468.3 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[O:7][CH:8]=1)([OH:3])=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:12][C:11]1([CH3:13])[C:14]([CH3:16])([CH3:15])[O:17][B:9]([C:6]2[O:7][CH:8]=[C:4]([C:1]([O:3][CH3:18])=[O:2])[CH:5]=2)[O:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)OB(c2cc(C(=O)O)co2)OC1(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1coc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 0.75 h

Procedure:
4-Carboxyfuran-2-boronic acid pinacol ester (200 mg, 0.840 mmol) was dissolved in CH2Cl2 (4 mL) and MeOH (0.444 mL). Trimethylsilyldiazomethane (0.840 mL, 1.680 mmol) was added dropwise. After 45 min, the reaction was quenched with AcOH dropwise until the yellow color disappeared. The reaction was concentrated in vacuo to give methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-furoate. 1H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H); 7.37 (s, 1H); 3.84 (s, 3H); 1.36 (s, 12H).
Reaction SMILES: [C:1]1([C:7]2([C:10]([O-:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-:16])([O-])=[O:14].[K+].OS(O)(=O)=O.[CH2:23](Cl)Cl>>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:10]([O:12][CH3:23])=[O:11])[CH2:9][CH2:8]2)=[CH:2][CH:3]=1)([O-:16])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C([O-])C1(c2ccccc2)CC1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol) in H2SO4/CH2Cl2 (40 mL/40 mL) was added KNO3 (12.8 g, 0.13 mol) in portion at 0° C. The mixture was stirred for 0.5 hr at 0° C. Ice water was added and the mixture was extracted with EtOAc (100 mL×3). The organic layers were dried with anhydrous Na2SO4 and evaporated to give methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (21 g, 68%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, J=2.1, 6.9 Hz, 2H), 7.51 (dd, J=2.1, 6.9 Hz, 2H), 3.64 (s, 3H), 1.72-1.69 (m, 2H), 1.25-1.22 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:35])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:15]=2[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[C:45]([CH:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][CH2:10][NH:11][C:12](=[O:35])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:15]=1[CH3:34])(=[O:47])[CH3:46]
Reactant: COc1ccc2c(c1)c(CC(=O)NCCCNC1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCC(NC1CCCCC1)C(C)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.100 g (0.2 mmol) of N-(3-cyclohexylaminoprop-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 1 mL of anhydrous dichloromethane was added 0.04 mL (0.24 mmol) of diisopropylethyl amine followed by 0.015 mL (0.2 mmol) of acetyl chloride. The reaction was stirred at room temperature for 20 hr then diluted with more dichloromethane (2 mL). The solution was washed with dilute aqueous citric acid (1 mL) before drying (Na2SO4), filtering and evaporating. The residue was purified by preparative HPLC to give the title compound. 1H NMR (CDCl3) δ 7.68 (2H, d), 7.39 (2H, d), 7.16 (1H, bt), 6.86 (1H, d), 6.79 (1H, d), 6.61 (1H, dd), 3.75 (3H, s), 3.57 (2H, s), 3.36 (1H, bt), 3.06 (4H, m), 2.33 (3H, s), 1.96 (3H, s), 0.9-1.8 (12H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.ClC(O[C:22]([Cl:24])=O)=O.[C:25](=O)(O)[O-:26].[Na+]>O1CCCC1>[Cl:24][CH2:22][C:25]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:26]
Reactant: O=C([O-])O
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)OC(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
13.8 g of 3-nitroaniline is dissolved in 500 ml of tetrahydrofuran. 30.5 ml of triethylamine and 19.4 g of chloroformic acid anhydride are added at 0° C. It is stirred for 12 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation and after purification by chromatography on silica gel, 20.0 g of the title compound is obtained.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]=2[CH:30]=1)=[O:9])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[C:15]2[CH:30]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])[CH:12]=[CH:13][C:14]=2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg (0.73 mM) of 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate dissolved in 20 ml of absolute methanol are treated with 500 mg of sodium methylate and stirred at room temperature for 1 hour. The mixture is then buffered with a small amount of acetic acid and concentrated. The residue is treated with methylene chloride/10% sodium bicarbonate solution, the aqueous solution is extracted several times with methylene chloride and the organic solution is dried over sodium sulphate, filtered and concentrated. After crystallisation from acetone, there is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which according to the IR spectrum is identical with a sample of this substance prepared in another manner (see Example 7).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH3:50][SH:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:50][S:51][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1
Reactant: CS
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 56.1 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g), methylmercaptan (15%, 0.51 g) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 6 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.22 g, 54%).
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(O)C>[CH3:19][O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5]
Reactant: COS(=O)(=O)OC
Reactant: CCC=C(C)C(O)CCCCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC=C(C)C(CCCCC)OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 75.8 %

Procedure:
5.0 g of 4-methyl-3-decen-5-ol dissolved in 25 ml of toluene are added dropwise over a period of 30 minutes at 80° C. while stirring to 1.54 g of a 55-60% sodium hydride dispersion in 25 ml of toluene. The mixture is stirred at 80° C. for 12 hours, cooled to 40° C. and treated dropwise with 5.6 g of dimethyl sulphate, the temperature again rising to 80° C. In order to complete the reaction, the mixture is stirred at 80° C. for a further 3 hours. After cooling to 40° C., 10 ml of ethanol are added thereto. The mixture is heated to boiling for a short period and then treated with cold 2N sodium hydroxide. The product is taken up in hexane, washed neutral, chromatographed on 250 g of silica gel in order to remove the oil of the sodium hydride dispersion used and the thus-obtained crude product is fractionally distilled. There are obtained 4.1 g (76% of theory) of 5-methoxy-4 -methyl-3-decene of boiling point 100°-105° C./14 Torr, nD20 =1.4337. Odour: very fresh, fruity, green, apple-like, blueberries, blackberries, herbaceous.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[S:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:30][CH2:29]2)[S:26][CH:27]=1
Reactant: Fc1ccccc1-c1csc(C2CCNCC2)n1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCC(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 57.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (102 mg, 0.377 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperidine (90 mg, 0.343 mmol) and diisopropylethylamine (0.120 ml, 0.686 mmol) in dimethylsulfoxide (1.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized form a mixed solvent of hexane and ethyl acetate to give the desired product (75.7 mg, 57.7%) as a solid.