Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:26])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.C(C1C(=O)C(Cl)=C(Cl)[C:31](=[O:32])C=1C#N)#N>O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:26])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[CH:31]=[O:32]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (250 mg, 0.55 mmol) in H2O (5.5 mL) is treated with DDQ (369 mg, 1.6 mmol) in EtOAc (0.5 mL), and stirred at rt for 2 h. The mixture is diluted with EtOAc (50 mL), washed with brine (50 mL), and extracted with saturated aqueous NaHCO3 (3×50 mL). The aqueous layer is acidified to pH 2 with HCl (conc.) and washed with Et2O (50 mL). The aqueous layer is neutralized with 10% aqueous NaOH and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by triturating in Et2O to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-formyl-indol-1-yl)-amide (87 mg, 43%). MS: 376 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.53 (s, NH, 1H), 10.00 (s, 1H), 9.34 (m, 1H), 8.81 (m, 1H), 8.66 (s, 1H), 8.48 (m, 1H), 8.04 (m, 1H), 7.86 (m, 1H), 7.72 (m, 1H), 7.61 (m, 1H), 7.27 (m, 1H), 2.80 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.[C:22]1(OC)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>ClCCl>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])[C:4]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccccc1
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole was cooled to 0° C. and 112 ml of trifluoroacetic acid was added. The solution was stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue was dissolved in 70 ml of acetone and the solution was adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate was added over 1 hour at pH 6.5-7.5. The mixture was stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation was chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gave 2.19 g of compound. Crystallization from ether-hexane yielded 1.125 g of the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.C.CCOCC.Cl>CO>[CH2:3]([O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH:2]([CH3:12])[CH3:1]
Reactant: C=C(C)COC1CCC(=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)COC1CCC(=O)CC1
Yield: 61.7 %

Procedure:
16.9 g (0.1 mole) of compound (16) were dissolved in 90 ml methanol. After adding 1.8 g of palladinised charcoal (10% Pd content), the solution was hydrogenated at room temperature and normal pressure. The catalyst was then removed and the solvent was distilled off under vacuum. The 15 g of crude product which were obtained were stirred for 1 hour at room temperature with 60 ml ether and 30 ml of 4N hydrochloric acid. This was followed by neutralisation with sodium hydrogen carbonate, separation of the ether phase, and extracting twice with ether. The ethereal solution was dried over sodium sulphate and the ether was distilled off. The 10.5 g of oil obtained were purified with 1:1 diisopropyl ether/n-hexane via a silica gel column. 6.85 g of compound (21) were obtained in a yield of 40% theoretical.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:34][C@H:35]1[C@@H:40]([OH:41])[CH2:39][CH2:38][N:37]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:36]1.[N+:52]([C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>C1COCC1>[F:34][C@H:35]1[C@H:40]([O:41][CH2:59][C:58]2[CH:62]=[CH:63][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=2)[CH2:39][CH2:38][N:37]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:36]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](F)C1
Temperature: 0 °C

Procedure:
To a solution of triphenylphosphine (120.1 g, 0.458 mol) in THF (2 L) was added DIAD (92.6 g, 0.458 mol) with stirring under nitrogen at 0° C. The resulting suspension was stirred for 40 min, and then a solution of benzyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate (58 g, 0.229 mol) and 4-nitrobenzoic acid (45.9 g, 0.275 mol) in THF was added slowly over 1.5 h. The resulting orange solution was allowed to warm to room temperature and stirred for 48 h. The mixture was concentrated under reduced pressure to a crude oil was purified by column chromatography (EtOAc:petroleum ether=1:40) to afford benzyl trans-3-fluoro-4-[(4-nitrobenzyl)oxy]piperidine-1-carboxylate as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][O:48][CH2:49][CH2:50][NH2:51].O>ClCCl>[CH3:47][O:48][CH2:49][CH2:50][NH:51][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:24]
Reactant: COCCN
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: COCCNC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 64 h
Yield: 25.8 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 409 μl (4.7 mmol) 2-Methoxy-ethylamine were added and the mixture was stirred for 24 h at room temperature. The reaction was poured into water and the precipitate filtered off. After drying of the residue in vacuo at 40° C., 91 mg (29%) of the title compound were isolated as a yellow solid. m.p. 254°-256° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@H:15]1[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:5])=[O:4])[CH3:2].[H][H]>CO.C1COCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([C@H:15]2[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)CC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)CC
Yield: 102.2 %

Procedure:
To 35F (2.2 g) in methanol (50 mL) and THF (30 mL) was added 10% Pd/C (580 mg). The mixture was hydrogenated with a hydrogen balloon for 6.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 35H (2.1 g, 95% yield). 1H NMR (500 MHz, DMSO-d6, 100° C.) δ ppm 0.88 (t, J=6.87 Hz, 3H) 1.16 (t, J=7.42 Hz, 3H) 1.26 (s, 9H) 2.07-2.13 (m, 2H) 3.13-3.21 (m, 2H) 3.49 (br s, 1H) 3.63-3.75 (m, 4H) 5.69 (d, J=8.25 Hz, 1H) 6.50-6.55 (m, 2H) 7.44 (d, J=8.79 Hz, 1H); LC-MS 427 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:31]([F:43])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[C@@H:31]([F:43])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C[C@@H]1F
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@@H](F)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1S*,2S*,4S*)-4-amino-2-fluorocyclohexyl]carbamate (example C22) the title compound is obtained as pale yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C1CCC1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.100 g, 0.271 mmol), TEA (1.0 mL), DCM (10 mL), cyclobutanecarbonyl chloride (0.041 g, 0.352 mmol) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.05 (m, 6H), 3.08 (m, 1H), 4.29 (m, 2H), 7.44 (m, 1H), 7.60 (m, 2H), 7.86 (m, 2H), 8.17 (m, 3H), 12.69 (s, 1H); MS (m/z): 451.07 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
2,4-Difluorobenzonitrile (5.00 g, 35.94 mmol), tert-butyl-1-piperazinecarboxylate (6.69 g, 35.92 mmol) and potassium carbonate (10.0 g, 72.4 mmol) were combined in dimethylsulfoxide (40 mL) and stirred at 150° C. overnight. The reaction mixture was cooled to ambient temperature, poured into water (150 mL) and extracted into ethyl acetate (150 mL). The extract was washed twice with water and once with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (2″×5″ silica gel). The column was flushed with 500 mL each 10% and 20% ethyl acetate/hexane and the product removed with an additional 500 mL of 20% ethyl acetate/hexane. Concentration gave 4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (3.28 g, 30%) which had mp 130.5-131.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[BrH:28].C(O)(=O)C>>[Br:28][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Cl)n2)c1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Br)n2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 45 %

Procedure:
The product from Step A (2.0 g, 6.6 mmol) was dissolved in a 30% solution of hydrobromic acid/acetic acid (18.0 mL). This mixture was stirred at room temperature for four days. The mixture was poured into aqueous 1M sodium carbonate (150 mL) and then extracted with ethyl acetate (5×50 mL). The combined extracts were dried (MgSO4) and then evaporated. The solid residue was recrystallized from hexane to afford 1.0 g (45%) of the title compound melting at 74°-76° C. 1H NMR (400 MHz, CDCl3) δ 10.64 (br s, 1H), 8.92 (s, 1H), 8.66 (s, 1H), 8.38 (m, 1H), 729-7.43 (s, 1H), 7.29-7.32 (m, 1H), 2.39 (s, 3H), 1.33 (s, 9H). Mass spec (EI) m/e 349 (1XBr).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[C:11]3[N:12]=[C:13]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:14]=[C:15]([C:16]4[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=4)[C:10]=3[CH2:9][CH2:8]2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH:39]([S:42](Cl)(=[O:44])=[O:43])([CH3:41])[CH3:40]>C(Cl)Cl>[CH3:29][C@H:24]1[CH2:25][O:26][CH2:27][CH2:28][N:23]1[C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[N:20][C:19]([NH2:22])=[N:18][CH:17]=2)[C:10]2[CH2:9][CH2:8][N:7]([CH:5]3[CH2:6][N:3]([S:42]([CH:39]([CH3:41])[CH3:40])(=[O:44])=[O:43])[CH2:4]3)[C:11]=2[N:12]=1
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CNC1)CC2
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)N1CC(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOC[C@@H]4C)nc32)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 53.1 %

Procedure:
To a suspension of 5-{7-(azetidin-3-yl)-2-[(3S)-3-methylmorpholin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine dihydrochloride (100 mg, 0.20 mmol) in DCM (5.0 mL) was added DIPEA (0.2 mL, 1.15 mmol). After a few minutes, the mixture became almost homogeneous, and a fine precipitation began to form. The reaction mixture was cooled to 0° C. and isopropylsulfonyl chloride (0.023 mL, 0.21 mmol) was added. The mixture was stirred at 0° C. for 45 min resulting in an amber solution. The mixture was concentrated to a minimum volume and the residue was purified by SFC column to give 50.4 mg (51%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2 H), 6.98 (s, 2 H), 4.80 (p, J=7.2 Hz, 1 H), 4.68-4.59 (m, 1H), 4.29-4.21 (m, 3 H), 3.98 (dt, J=7.9, 4.4 Hz, 2 H), 3.88 (dd, J=11.1, 3.0 Hz, 1 H), 3.72-3.65 (m, 3 H), 3.56 (dd, J=11.3, 2.9 Hz, 1 H), 3.40 (dt, J=11.7, 2.8 Hz, 1 H), 3.28-3.21 (m, 1H, partially overlapped with water), 3.15 (t, J=8.2 Hz, 2 H), 3.07 (dt, J=12.9, 3.7 Hz, 1 H), 1.24 (d, J=6.8 Hz, 6 H), 1.16 (d, J=6.7 Hz, 3 H). m/z (APCI+) for C21H30N8O3S 475.2 (M+H)+.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=1.[Br:9]N1C(=O)CCC1=O>ClCCl>[Br:9][C:4]1[C:5](=[O:8])[CH2:6][CH2:7][C:3]=1[O:2][CH3:1]
Reactant: COC1=CC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC1=C(Br)C(=O)CC1
Yield: 76.2 %

Procedure:
A mixture of Example 7A (500 mg, 4.46 mmol) and N-bromosuccinimide (794 mg, 4.46 mmol) in dichloromethane (5 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated in vacuo. The residue was purified on a silica column (dichloromethane/methanol=200:1, v/v) to afford the title compound (650 mg, 3.40 mmol, 76% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.12 (s, 3H), 2.79-2.82 (m, 2H), 2.62-2.65 (m, 2H); LC/MS (ESI) m/z 191 (M+H)+.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].CC(C)(OC([N:47]1[C:51]2[CH:52]=[CH:53][C:54]([CH:56]=O)=[CH:55][C:50]=2[N:49]=[N:48]1)=O)C>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:56]/[C:54]1[CH:53]=[CH:52][C:51]2[NH:47][N:48]=[N:49][C:50]=2[CH:55]=1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)n1nnc2cc(C=O)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc2[nH]nnc2c1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.5 mL, 3.97 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 1.00 g, 1.89 mmol) in tetraliydrofuran (3 mL) at −20° C. After 10 min, a solution of 1-(1,1-dimethylethoxycarbonyl)-1H-benzotriazole-5-carboxaldehyde (Example 40; 467 mg, 1.89 mmol) in tetrahydrofuran (3 mL) was added. The solution was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was dissolved in a mixture of trifluoroacetic acid/dichloromethane (1:1; 4 mL). After the solution was stirred at room temperature for 2 h, the solvent was evaporated and the residue co-evaporated with toluene (2×5 mL) to remove residual trifluoroacetic acid. Ethyl acetate (20 mL) was added and the solution was washed with 5% sodium bicarbonate solution (20 mL). After the aqueous layer was back extracted with ethyl acetate, the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The residual material was chromatographed over silica gel (5-10% methanol/dichloromethane) to give (Z)-3-(1H-benzotriazol-5-yl)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (690 mg, 66% yield) as a colorless solid.
Reaction SMILES: C(O)CO.[C:5]([CH:7]([C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)C(OC)=O)#[N:6].[OH-].[K+]>O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:12]1([CH2:7][C:5]#[N:6])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: COC(=O)C(C#N)C1(c2ccccn2)CCOC2(CCCC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: N#CCC1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 120 °C
Yield: 82.6 %

Procedure:
Ethylene glycol (300 ml) was added to methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.43 g, 49 mmol) followed by potassium hydroxide (5.5 g, 98 mmol), the resulting mix was heated to 120° C., after 3 h, the reaction mix was cooled and water (300 ml) was added, the product was extracted by Et2O (3×400 ml), washed with water (200 ml), dried (Na2SO4) and concentrated, the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV to give 2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (10.37 g, 82% yield, m/z 257.0 [M+H]+ observed).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (4.1 g), (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (2.36 g) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 27%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[S].S>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C1=C(C)NC=CC1c1ccccc1
Agent: S
Agent: [S]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)ccnc1C
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 0.32 mol ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate in 50 ml of methylene chloride was added 16 g (0.5 mol) of sulfur. The temperature of the well-stirred dark solution was raised over a period of about 30 minutes to 170°-180° C. When the development of hydrogen sulfide had subsided, the reaction mixture was cooled to room temperature, taken up in toluene, and filtered through Celite filter aid. The filtrate was concentrate under vacuum and the residue chromatographed on silica gel, eluting with ethyl acetate/hexane to yield 61.7 g of ethyl 2-methyl-4-phenyl-3-pyridinecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Br:25])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1
Reactant: Cc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1cc(Br)ccc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of (5-bromo-2-chlorophenyl)(p-tolyl)methanone (intermediate AG) (16 g, 48.9 mmol) in CCl4 (80 mL), NBS (10.08 g, 57 mmol) and AIBN (0.848 g) was added. Then the mixture was heated to 90° C. After 3 h, CCl4 was removed under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed 1× with HCl (1M) and 2× with brine prior to drying over Na2SO4. Solvent was removed under reduced pressure to obtain crude intermediate AH (20.75 g).