Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:61]([O:63][CH2:64][Cl:65])=[O:62]>N1C=CC=CC=1.C(OCC)(=O)C>[C:61](=[O:62])([O:63][CH2:64][Cl:65])[O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reactant: O=C(Cl)OCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)OCCl)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of the product from Example 111 (0.050 g, 0.062 mmol) in pyridine (0.60 mL) at room temperature was added chloromethyl chloroformate (0.007 mL, 0.079 mmol), and the mixture was stirred for 30 minutes. Additional chloromethyl chloroformate (0.007 mL) was added and the reaction was stirred for 30 minutes. The reaction was diluted with ethyl acetate and washed with dilute NaHCO3 and brine. The organic was dried over MgSO4, filtered and evaporated to give the title compound (0.047 g, 84% yield), which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=O)[CH2:3][CH2:2]1.[CH3:17][NH:18][NH2:19]>CN(C)C=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:18]([CH3:17])[N:19]=2)[CH2:3][CH2:2]1
Reactant: O=C(C#CC1CC1)c1ccc([N+](=O)[O-])cc1
Reactant: CNN
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C2CC2)cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Cyclopropyl-1-(4-nitrophenyl)prop-2-yn-1-one (500 mg, 2.323 mmol) was dissolved in N,N-dimethylformamide (7.75 mL), and the solution was chilled to 0° C. Methylhydrazine (118 mg, 2.56 mmol) was added dropwise. The mixture was stirred overnight at room temperature then diluted with water (25 mL) and stirred for 45 minutes. The resulting precipitate was collected by filtration to give the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)(=O)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C>Cl>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(C)cn1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CO)nc1
Yield: 83.5 %

Procedure:
2-Acetoxymethyl-5-methyl pyridine (30 g, 182 mmol) was dissolved in hydrochloric acid (100 mL, 4 N). The mixture was heated under reflux, until TLC (silica gel; triethylamine:ethyl acetate:petroleum ether 40-60=1:9:19) showed complete absence of the acetate (normally 1 hour). The mixture was cooled, brought to pH>11, extracted with dichloromethane (3×50 mL) and the solvent removed in vacuo. Pure 2- hydroxymethyl-5-methyl pyridine (18.80 g, 152 mmol, 84%) was obtained by Kugelrohr distillation (p=20 mm Hg, T=130° C.) as a slightly yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1(OB(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2nccs2)cc1
Yield: 67.2 %

Procedure:
2-Bromothiazole (1.2 mmol, 0.11 mL) and phenylboric acid (1.2 mmol, 0.146 g) were added to a solution of potassium carbonate (2M, 1.2 mL) and ethanol (0.6 mL) in deoxygenated toluene (12 mL). The resulting mixture was degassed for 30 minutes, then tetrakistriphenylphosphine palladium (0.036 mmol, 0.042 g) was added and the solution heated at reflux for 48 hours. The solids were removed by filtration and the solution extracted with toluene (5x), dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (hexane followed with 5% ethyl acetate/hexane and then 10% ethyl acetate/hexane) to afford 0.13 g (69%) of 2-phenylthiazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:34])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:34])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(F)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 26.1 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile (2.2 g, 8 mmol) prepared in Example 65a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[CH:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]#[CH:15])=[CH:17]1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C=Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) in dimethylformamide (25 ml) was added 3-ethenylindole (2.9 g) and potassium carbonate (2.84 g), the mixture was heated at 90° C. for 3 hours under an atmosphere of nitrogen and then left to stir overnight at room temperature. The reaction was diluted with water (100 ml) and extracted with hexane (2×100ml). The organic fractions were separated, combined, evaporated to dryness and purified by column chromatography on silica gel (300 g) eluted with hexane:ethylacetate (97:3) to give the title compound as a white solid (1.3 g), m.p. 120-122 ° C.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[N:22]2)C(OC(C)(C)C)=O)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH2:16][C:17]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[N:22]2
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Reaction time: 1 h

Procedure:
13.8 9 (29.7 mmol) of 5-[di-(tert-butoxycarbonyl)amino]methyl-7-nitro-2,3-dimethoxyquinoxaline are stirred at room temperature for 8 hours in 60 ml of trifluoroacetic acid. The reaction mixture is concentrated under reduced pressure and the red oil is well stirred at 0° for one hour with 1N potassium carbonate. The yellow crystals are filtered off, washed with 100 ml of water and 100 ml of a 1:1 mixture of ethyl acetate and hexane, and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[CH:24]=[C:23]([CH2:25]Cl)[CH:22]=[CH:21][N:20]=2)=[CH:13][C:12]=1[O:27][CH3:28]>>[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[CH:24]=[C:23]([CH2:25][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH:22]=[CH:21][N:20]=2)=[CH:13][C:12]=1[O:27][CH3:28]
Reactant: NC(=O)C1CCNCC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Product: COc1cc(-c2cc(CN3CCC(C(N)=O)CC3)ccn2)cc(OC)c1Cl

Procedure:
Piperidine-4-carboxamide (301 mg) and 2-(4-chloro-3,5-dimethoxyphenyl) 4-chloromethyl pyridine (600 mg) were coupled in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]3[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[C:33]([N:35]=[C:36]=[O:37])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39].C1COCC1>>[Cl:27][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:33]2[CH:32]=[CH:31][C:30]([O:38][CH3:39])=[C:29]([Cl:28])[CH:34]=2)=[O:37])=[CH:7][C:6]=1[C:8]1[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]2[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Reactant: COc1ccc(N=C=O)cc1Cl
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(-c3cc4cnc(NCCN(C)C)nc4n(OC)c3=O)c2)cc1Cl
Temperature: 25 °C
Yield: 56 %

Procedure:
In a 3 ml vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin -7(8H)-one (165 μmol). A solution of 2-chloro-4-isocyanato-1-methoxybenzene in THF (2 mL, 129 mmol) was added, and the mixture was stirred at room temperature over night. The solvent was allowed to evaporate over night, and the remaining solid was dissolved in DMSO, transferred to maximum recovery HPLC vials and purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 1-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(3-chloro-4-methoxyphenyl)urea as a solid (56%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc(F)cc4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-fluorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11FN4O3, 350.1; m/z found, 351.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 1H), 12.92 (br s, 1H), 8.98 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 8.16 (dd, J=8.5, 2.2 Hz, 1H), 7.88-7.82 (m, 2H), 7.79 (s, 1H), 7.37-7.32 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[OH:11])[CH3:3].C(Cl)Cl.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:17])[OH:11])[CH3:1]
Reactant: CN(C)CC1CCCCC1(O)c1cccc(C(=O)O)c1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1cccc(C2(O)CCCCC2CN(C)C)c1
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
A sample of 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzoic acid (0.1 g, 0.36 mmol), CH2Cl2 (5 mL), and diethylamine (0.08 mL, 0.36 mmol) was placed into a flask and stirred for 5 min. To the reaction was added HATU (0.13 g, 0.36 mmol) and stirring was continued for 2 h. Water was added and the organic phase was separated, washed again with water, dried (Na2SO4), and filtered. The filtrate was evaporated in vacuo and the residue passed through a silica gel column (90:10:1, CH2Cl2:MeOH:NH4OH) to give 42 mg (35%) of 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-N,N-diethyl-benzamide: MS m/z=333 (MH+); 1H NMR (CDCl3) δ 7.7-7.2 (Ar, 4H), 3.6 and 3.2 (bq, 4H), 2.4 (dd, 1H), 2.1 (s, 6H), 2.0-1.5 (m, 10H), 1.1 (bt, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1>O>[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:9][CH3:10])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(OC)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: O
Product: COc1ccc(OC)c(C(=O)Cc2cccc(Br)c2)c1
Temperature: 75 °C
Yield: 64.7 %

Procedure:
A mixture of 1,4-dimethoxybenzene (7.02 g, 50.8 mmol), 2-(3-bromophenyl)acetic acid (6.07 g, 28.2 mmol) and PPA (40 mL) was heated at 75° C. overnight and cooled to 50° C. Water (60 mL) was added, and the mixture was allowed to cool to room temperature. Additional water (100 mL) was added, and the mixture was extracted with DCM (2×200 mL). The organic phase was washed (100 mL H2O, 100 mL brine), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified on a silica gel column to give 2-(3-bromophenyl)-1-(2,5-dimethoxyphenyl)ethanone (6.12 g, 65%). 1H NMR (DMSO-d6): δ 7.45-7.41 (m, 2H), 7.29-7.24 (m, 1H), 7.23-7.19 (m, 1H), 7.13 (m, 2H), 7.11 (m, 1H), 4.29 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H); LCMS: 335.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:17]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][Br:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)Cc1ccc(C(C)(C)C)cc1
Reactant: BrP(Br)Br
Product: CC(CBr)Cc1ccc(C(C)(C)C)cc1
Reaction time: 16 h

Procedure:
300.2 g of 3-(p-tert.butyl-phenyl)-2-methyl-propanol are added dropwise over a period of 2 hours at 20°-30° C. to 218.6 g of phosphorus tribromide and the mixture is left to stand for 16 hours. The mixture is subsequently heated to 55°-60° C. over a period of 1.5 hours, cooled to ca 10° C. and cautiously poured on to ice. The aqueous solution is exhaustively extracted with ether, the combined ether phases are washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. By fraction distillation there is obtained pure 3-(p-tert.butyl-phenyl)-2-methyl-propyl bromide of boiling point 104° C./0.025 Torr.
Reaction SMILES: C(OC(N[CH:9]([OH:19])[C@H:10](C)[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O)(C)(C)C.CC(C)([O-])C.[K+].O.[CH3:27][N:28](C)[CH:29]=[O:30]>>[CH3:27][N:28]1[C@H:10]([CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][O:19][C:29]1=[O:30]
Reactant: CN(C)C=O
Reactant: C[C@H](CCc1cccs1)C(O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CN1C(=O)OC[C@H]1CCc1cccs1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
(2R)-t-Butoxycarbonylamino-2-methyl-4-(thiophen-2-yl)-1-butanol (15.4 g, 53.9 mmol) obtained in Example 67(b) was dissolved in N,N-dimethylformamide (200 ml), and potassium t-butoxide (9.07 g, 80.8 mmol) was added thereto in an ice bath followed by stirring for 10 minutes in an ice bath and subsequently for 40 minutes at room temperature. To the reaction solution was added water, and then the solution was extracted with ethyl acetate, and after the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:1) to afford the tide compound (11.5 g, 100% yield) as a white solid. The data obtained from analytical instruments were in accord with that obtained in Example 66.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[NH2:7][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(N)c1
Solvent: CCO
Product: CCOC(=O)C(=CNc1cccc(N)c1)C(=O)OCC
Reaction time: 30 h

Procedure:
10.8 Grams of m-phenylenediamine are dissolved in 80 ml of ethyl alcohol, 21.6 grams of diethyl ethoxymethylenemalonate are added and the mixture is heated under reflux for 40 minutes. After filtration hot, 50 ml of water are added and the mixture is left for 24 to 36 hours at room temperature with stirring. The precipitate formed is filtered off, washed with an ethanol/water (1:1) mixture and dried at 60° C. The product is recrystallized in a benzene/hexane (2:1) mixture and 10.5 grams of a solid are obtained, of melting point 71°-74° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)([OH:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8]1)[CH3:5].[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>O1CCCC1.O>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[CH3:5][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)([OH:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8]1)[CH3:3]
Reactant: CN(C)CC1CC2(CCC1(O)c1cccc(F)c1)OCCO2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CC(=O)CCC1(O)c1cccc(F)c1
Reaction time: 16 h
Yield: 47.1 %

Procedure:
11.4 ml of hydrochloric acid (32%, excess) were added rapidly at 0° C. to a solution of 7-dimethylaminomethyl-8-(3-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol hydrochloride (10.83 g, 31.3 mmol) in tetrahydrofuran/water mixture, and stirring was then carried out for 16 hours at RT. The mixture was adjusted to pH 11 with 32% sodium hydroxide solution, and extraction was carried out with ether. After evaporation of the solvent in vacuo, the residue was taken up in diisopropyl ether and EE, and the corresponding salt was precipitated by addition of methanesulfonic acid (1.88 ml, 28.9 mmol). 4.92 g (53%) of the product were obtained in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:11]Br.[O-]S([O-])=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C.[Fe]>[Br:11][C:5]1[C:6]2[C:10](=[N:9][O:8][N:7]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1cccc2nonc12
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(Br)c2nonc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
4-Chlorobenzo[c][1,2,5]oxadiazole (1.0 g, 6.5 mmol) was treated with iron powder (14 mg, 0.2 mmol), stirred and heated to 50° C. and then treated in portions with bromine (1.1 g, 7.1 mmol) to produce a homogeneous red melt solution. The flask was fitted with a reflux condenser and the temperature was raised to 85° C. and stirred for 60 min. An additional 450 mg of bromine were added, heating was continued for 1 h more and then the mixture was allowed to stand for 18 h at 20° C. The solid contents of the flask were dissolved in 15 mL dichloromethane and stirred for 30 min with 15 mL saturated Na2SO3 solution. The mixture was diluted with 30 mL ethyl acetate and the organic phase was washed with 15 mL saturated NaCl, dried (Na2SO4) and concentrated under vacuum. The material was chromatographed on silica with a 0-7% ethyl acetate-hexane gradient to give the title compound as a white solid (1.4 g; 93%): mp 81-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.5 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H); EIMS m/z 232.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([C@@H](C3C=CC=CC=3)C)[CH2:14]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>ClCCl>[CH2:30]([O:29][C:27]([N:15]1[CH2:16][CH2:17][CH:13]([CH2:12][C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)[CH2:14]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](c1ccccc1)N1CCC(CC2(NC(=O)OC(C)(C)C)CC2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CC2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (1.234 g, 3.582 mmol) was dissolved in dry dichloromethane (20 ml) to which, under ice cooling, was subsequently added dropwise benzyl chloroformate (1,278 μl, 8.955 mmol). After 8 hours of stirring at room temperature, the reaction solution was concentrated under a reduced pressure. The thus obtained residue was subjected to a flash silica gel chromatography, and 959 mg (71.5%) of the title compound was obtained from an eluate of n-hexane:ethyl acetate=2:1 as a colorless oil component.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].N[C:13]1N=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[CH3:11][C:7]1[CH:8]=[CH:9][N:10]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:20][CH2:19][C:18]=3[N:1]=[C:2]2[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccnc(N)c1C(=O)O
Reactant: Nc1ncccc1C(=O)O
Product: Cc1ccn2c(=O)c3c(nc2c1C(=O)O)CCC3

Procedure:
By substituting 2-amino-4-methylnicotinic acid for the 2-aminonicotinic acid in Example 4, there is obtained the named compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4′-bromo-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N=C(N)NNC(=O)c1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a solution of hydrazinecarboximidamide bicarbonate salt (2.3 g, 31.05 mmol) in pyridine (70 ml) was added dropwise 4-chlorobenzoyl chloride (4.5 g, crude) in DCM (20 ml). After stirring overnight at 15° C., the resulting mixture was concentrated under vacuum, quenched by the addition of water (20 ml) and adjusted to pH 13 with sodium hydroxide solution (10N). The product was collected by filtration and dried to give 2-(4-chlorobenzoyl)hydrazinecarboximidamide as a white solid (2.1 g, crude).