Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9](=[O:27])[CH2:10][CH:11]([NH:19]C(=O)OC(C)(C)C)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:19][CH:11]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH2:10][C:9]([NH2:8])=[O:27]
Reactant: CC(C)(C)OC(=O)NC(CC(N)=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)CC(N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
HCl (4M) in 1,4 dioxane (1.674 mL, 6.69 mmol) was added to tert-butyl 3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamate (Intermediate 106) (200 mg, 0.67 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 4 hours. The reaction mixture was evaporated and was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford 3-amino-3-(4-chlorophenyl)propanamide (46.0 mg, 34.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][NH:19][CH3:20]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:19]([CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Yield: 100.3 %

Procedure:
A solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.754 mmol) and excess dimethylamine (3.77 mL, 7.54 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford 2-chloro-N,N-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (207 mg, 0.756 mmol, 100% yield). LC-MS (M+H)+=274.2.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]([NH2:11])([CH3:10])[CH3:9]>C1C=CC=CC=1>[CH:8]([NH3+:11])([CH3:10])[CH3:9].[O:1]=[CH:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: O=CCCC(=O)O
Reactant: CC(C)N
Solvent: c1ccccc1
Product: CC(C)[NH3+]
Product: O=CCCC(=O)[O-]
Temperature: 25 °C

Procedure:
100 Mg. of 4-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)-4-oxobutyric acid in 15 ml. of hot benzene is treated with 60 mg. of isopropyl amine. The solution is allowed to cool to room temperature and the product is filtered off, washed with ether and dried to yield isopropylammonium 4-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)-4-oxobutyrate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:54]([O:56]CC)=[O:55])[CH2:11][CH:10]1/[CH:12]=[CH:13]/[C:14]1[C:15]([CH3:53])([CH3:52])[C@H:16]2[C@:29]([CH3:32])([CH2:30][CH:31]=1)[C@@H:28]1[C@:19]([CH3:51])([C@@:20]3([CH3:50])[C@H:25]([CH2:26][CH2:27]1)[C@H:24]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]1([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]1)[CH2:22][CH2:21]3)[CH2:18][CH2:17]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:54]([OH:56])=[O:55])[CH2:11][CH:10]1/[CH:12]=[CH:13]/[C:14]1[C:15]([CH3:53])([CH3:52])[C@H:16]2[C@:29]([CH3:32])([CH2:30][CH:31]=1)[C@@H:28]1[C@:19]([CH3:51])([C@@:20]3([CH3:50])[C@H:25]([CH2:26][CH2:27]1)[C@H:24]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]1([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]1)[CH2:22][CH2:21]3)[CH2:18][CH2:17]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.4 %

Procedure:
To a solution of ethyl 1-((tert-butoxycarbonyl)amino)-2-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)cyclopropanecarboxylate (12 mg, 0.015 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 25° C. for 2 h. The crude product was purified by prep HPLC (method 4) to give 1-((tert-butoxycarbonyl)amino)-2-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)cyclopropanecarboxylic acid as a white solid (1 mg, 8.63%). MS: m/e 796.55 (M+H)+, 2.57 min (method 2). 1H NMR (400 MHz, METHANOL-d4) δ 7.37-5.41 (m, 2H), 5.36-5.10 (m, 1H), 4.73 (br. s., 1H), 4.57 (br. s., 1H), 3.19-2.97 (m, 8H), 2.80-2.62 (m, 4H), 2.58-2.41 (m, 1H), 2.36-1.78 (m, 7H), 1.72 (s, 3H), 1.69-1.21 (m, 25H), 1.16 (m, 6H), 1.09-1.00 (m, 6H), 0.98-0.82 (m, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58](=[O:72])[NH:59][C@H:60]([C:65](=[O:71])[NH:66][CH2:67][CH2:68][CH:69]=O)[CH2:61][CH:62]([CH3:64])[CH3:63])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:69][CH2:68][CH2:67][NH:66][C:65](=[O:71])[C@H:60]([CH2:61][CH:62]([CH3:64])[CH3:63])[NH:59][C:58](=[O:72])[O:57][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reaction time: 3.5 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxy-propanoate (200 mg, 0.277 mmol, obtained from Reference Example 6) and [(1S)-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (111 mg, 0.35 mmol, obtained from Reference Example 16) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (4 drops) and sodium triacetoxyborohydride (117 mg, 0.55 mmol) were added, and the resulting solution was stirred under nitrogen for an additional 3.5 hours. The reaction mixture was basified to pH 9 with sodium carbonate aqueous solution, and the aqueous layer was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (276 mg, 97%), as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2C)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[CH:21]=[CH:22][S:48][C:25]=3[CH2:24][CH2:23][C@H:19]2[CH3:20])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@H]1C

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.35-7.30, 7.10, 6.90, 5.18, 4.60, 2.85, 2.66, 2.49, 2.05, 1.82, 1.29-1.12; HRMS (FAB) calcd for C23H25Cl2N3S+H 446.1224, found 446.1230. Anal. Calcd for C23H25Cl2N3S: C, 61.88; H, 5.64; N, 9.41; Cl, 15.88; S, 7.18. Found: C, 62.04; H, 5.77; N, 9.04.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>>[CH3:27][C:21]1[C:20]([Cl:19])=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: CC(C)(C)C(=O)OCOC(=O)c1cccnc1Cl
Agent: Cl
Product: Cc1c(Cl)cccc1Nc1ncccc1C(=O)OCOC(=O)C(C)(C)C
Temperature: 140 °C

Procedure:
Into a suitable flask, pivaloyloxymethyl 2-chloro-3-pyridinecarboxylate prepared according to Example 2, supra (21.7 g) and 3-chloro-2-methylaniline (28.4 g) are charged. To begin the reaction the mixture is heated to 140° C. During the reaction the temperature of the reaction mixture rises to 190° C. When reaction is completed, the temperature diminishes. The reaction mixture is then cooled to room temperature. Diluted hydrochloric acid is added to the cooled mixture and the precipitated compound ground into small particles and suspended in the reaction mixture. The solid is separated by filtration and the cake washed with water. Then the washed solid is dissolved in hot methanol and recrystallized by cooling the methanolic solution. The crystallized product is separated and dried under vacuum, at a temperature of 40° C. Pivaloyloxymethyl 2-(2'-methyl-3'-chloro-anilino)-3-pyridinecarboxylate (m.p. 90°-91° C.) is so obtained, with a yield of 22.5 g (77.6% of theory).
Reaction SMILES: [Se](=O)=O.O.C([C:8]1([Cl:14])[CH2:12][CH:11]=[C:10]([Cl:13])[S:9]1)(=O)C.[O:15]1CC[O:18][CH2:17][CH2:16]1>>[Cl:13][C:10]1[S:9][C:8]([Cl:14])=[CH:12][C:11]=1[C:17](=[O:18])[CH:16]=[O:15]
Reactant: CC(=O)C1(Cl)CC=C(Cl)S1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: O=CC(=O)c1cc(Cl)sc1Cl
Temperature: 60 °C

Procedure:
A 31.4 g portion of selenium dioxide was added to a solution of 75 ml of dioxane and 10 ml of water and warmed to 60° C. with stirring. A 50 g portion of 2-acetyl-2,5-dichlorothiophene was added and the mixture was stirred at reflux for 7 hours. The mixture was diluted with dioxane, filtered and evaporated to dryness. Ether was added, then heptane and the mixture refrigerated. The solid was collected, giving 30.1 g of 2,5-dichloro-α-oxo-3-thiopheneacetaldehyde.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]1[C@@H:40]2[CH2:41][C@@H:37]([CH2:38][CH2:39]2)[C@@H:36]1[CH2:42][OH:43]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12]/[C:11](=[N:13]/[O:14][CH3:15])/[CH2:10][C@H:9]2[C:16]([NH:34][C@H:35]2[C@@H:36]([CH2:42][OH:43])[C@H:37]3[CH2:41][C@@H:40]2[CH2:39][CH2:38]3)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CO/N=C1\C[C@@H](C(=O)N[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and [(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=462.
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:27]([O:28][CH3:29])=[CH:26][C:10]2[N:11]([CH3:25])[C:12](=[O:24])[CH2:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:9]=2[CH:8]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][O:28][C:27]1[C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]2[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])=[N:14][CH2:13][C:12](=[O:24])[N:11]([CH3:25])[C:10]=2[CH:26]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1-c1ccccc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Temperature: 120 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To 5 mL of degazed DMF were added 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 (200 mg, 0.52 mmol), benzene boronic acid (160 mg, 1.32 mmoles), tripotassium phosphate (300 mg, 1.42 mmol), Pd(PPh3)4 (30 mg, 0.03 mmoles). The mixture was stirred for 16 hours at 120° C. under nitrogen atmosphere. The working solution was diluted ten times with water and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was chromatographied: eluant: CH2Cl2/Et2O: 1/1. The obtained compound was crystallised from ether/pentane to afford the title compound (118 mg): white solid, (yield=60%).
Reaction SMILES: [OH:1]O.[OH-].[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1>CO>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([NH2:13])=[O:1])=[N:10][CH:11]=1
Reactant: N#Cc1ccc(N)cn1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
A 18 ml vial was loaded with a mixture of 30% H2O2 (1 ml), 3N NaOH (3 ml) and MeOH (2.5 ml). To this mixture 5-Amino-pyridine-2-carbonitrile (450 mg, 3.78 mmole) was added at room temperature. Reaction mixture was stirred at rt for 45 minutes, TLC showed the starting material to be consumed. The mixture was diluted with water and filtered; the solid was washed with water and dried to give 480 mg product, 92% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][NH:17][O:18][CH3:19].C(Cl)Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:16][N:17]([O:18][CH3:19])[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccoc1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a suspension of furan-3-carboxylic acid (36 g, 0.32 mol) in 250 ml of toluene was added 49 g (0.385 mol) of oxalyl chloride and 1 drop of pyridine, and the mixture was heated at 80°-90° C. for 1.5 h. The mixture was cooled to room temperature, N,O-dimethylhydroxylamine hydrochloride (35 g, 0.36 mol), 4-dimethylaminopyridine (DMAP, 1.8 g, 0.0147 mol), and 600 ml of methylene chloride were added. The mixture was cooled to 0° C., 68.4 g of pyridine was added slowly, the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was filtered, and the filtrate was washed with water, 5% aqueous dimethylaminopropylamine, water, 6N HCl solution, water, and brine. The organic layer was dried and concentrated in vacuo, and the residue was distilled (b.p. 85°-87° C./0.2 mm) to afford 44 g (88.7%) of 3-(N-methyl-N-methoxycarbamoyl)furan.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:33]([F:38])=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH2:20][CH:31]([C:30]1[C:33]([F:38])=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:29]=1)[OH:32]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1cc(F)c(C=O)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(F)c(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of diisopropylamine (0.16 g) in tetrahydrofuran (2 mL) at −78° C. is added a 2.5 N solution of n-butyl lithium in hexanes (0.62 mL). The solution is allowed to warm to −10° C. and cooled back to −78° C. A solution of 3,5-dichloro-4-methylpyridine (0.25 g) in dry tetrahydrofuran (4 mL) is added, stirred for 0.5 hours at −60° C. and treated with 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (0.25 g) in dry tetrahydrofuran (4 mL). The reaction mixture is allowed to warm to room temperature over 1 hour and stirred overnight. The mixture is treated with 2N ammonium chloride (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried (magnesium sulfate) and evaporated to give 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol (0.22 g). [NMR (CDCl3): 8.44 (s, 2H), 6.97(d, 1H, J=7 Hz), 6.56 (d, 1H, J=12 Hz), 5.34 (m, 1H), 4.74 (m, 1H), 3.83 (s, 3H), 3.5 (dd, 1H, J=8 Hz, 8 Hz), 3.32 (dd, 1H, J=5 Hz, 6 Hz), 2.07 (d, 1H, J=6 Hz), 1.93-155 (m, 8H)].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[CH:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:27]([CH:23]4[CH2:26][CH2:25][CH2:24]4)=[O:28])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: O=C(O)C1CCC1
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1CNC(=O)C1CCC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(Aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with cyclobutanecarboxylic acid similar to as described in example 2 with non-critical modifications to afford crude 10-bromo-3-(cyclobutanecarboxamidomethyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-methyl-3-butyne-ol via General Procedure F to afford 12 mg (29.3%) of 3-[(cyclobutanecarbonylamino)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetra hydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:20]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)(=O)[CH3:21].C(=O)(O)[O-:32].[Na+]>O1CCCC1>[CH2:2]([C:1]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][N:5]=2)[NH:28][C:27]=1[C:26]1[CH:29]=[CH:30][C:23]([CH2:20][CH:21]=[O:32])=[CH:24][CH:25]=1)[CH3:3]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: O=C([O-])O
Reactant: CCCc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(CC=O)cc2)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 30.3 %

Procedure:
A solution of n-propylpyrazine (compound 2, 912 mg, 7.46 mmol) in tetrahydrofuran (5 mL) was added drop-wise, over a period of seven minutes, to a solution of sodium bis(trimethylsilyl)amide (2M solution in THF; 13 mL, 26 mmol, 3.5 equiv) at 20° C. A deep, purple-red solution was obtained and the temperature fell to 16.4° C. A solution of 4-acetylbenzonitrile (compound 3, 1.08 g, 7.4 mmol) in tetrahydrofuran (5 mL) was added, over a period of 18 minutes, at 13.3° C. The temperature fell to 12.6° C. and a brown solution ensued. The mixture was stirred at room temperature for one hour, heated to about 35° C. for six hours, then left to stir at room temperature for about 60 hours. The mixture was poured into aqueous saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (2×150 mL). The ethyl acetate was washed with water (100 mL) and concentrated on the Buchi at a bath temperature of 40° C. and from 80 to 10 torr to give a deep-yellow solid. The solid was triturated with diethyl ether (25 mL), filtered and washed with ether (25 mL). The solid was air dried to give 600 mg (30.3%) of compound 4 as a yellow solid: 1H NMR (300 MHz, CDCl3, FIG. 1) δ 8.5 (1H, d, J=2 Hz), 8.15 (2H, d, J=8 Hz), 8.1 (1H, d, J=3 Hz), 7.9 (2H, d, J=8 Hz), 3.1 (2H, q, J=9 Hz), 2.7 (3H, s), 1.4 (3H, t, J=9 Hz).
Reaction SMILES: CC1C=CC=CC=1C(O)=O.C(OCC)(=O)C.CCCCCC.[Si]([O:30][C:31]1[CH:32]=[C:33]([O:62][Si](C(C)(C)C)(C)C)[C:34]2[CH2:45][S:44][CH2:43][C@@H:42]([C:46]([O:48][CH3:49])=[O:47])[NH:41][C:40](=[O:50])[C@@H:39]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:38][O:37][C:36](=[O:59])[C:35]=2[C:60]=1[CH3:61])(C(C)(C)C)(C)C.[F-].[NH4+]>CO>[OH:30][C:31]1[CH:32]=[C:33]([OH:62])[C:34]2[CH2:45][S:44][CH2:43][C@@H:42]([C:46]([O:48][CH3:49])=[O:47])[NH:41][C:40](=[O:50])[C@@H:39]([NH:51][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:38][O:37][C:36](=[O:59])[C:35]=2[C:60]=1[CH3:61]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: Cc1ccccc1C(=O)O
Agent: [F-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,5-Bis (tert-butyldimethylsilyloxy)-6-[[[(R)-2-[(S)-1-tertbutoxyformamido)-3-hydroxypropionylamino]-2-methoxycarbonylethyl]thio]methyl]-2-methylbenzoic acid was lactonized in analogous manner to the procedure described in Example 1 to afford, upon chromatographic purification on silica gel using ethyl acetate/hexane (1: 3, v/v) as eluent, tert-butyl (4R, 7S)-12,14-bis (tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-4-methoxycarbonyl-11-methyl-6, 10-dioxo-9, 2,5-benzooxathiaazacyclododecine-7-carbamate as a pale yellow foam. To a solution of 21.4 g of this material in 300 ml of methanol were added 3.3 g of ammonium fluoride, and the mixture was stirred for 30 minutes at room temperature. The solvent was evaporated in vacuo. The residue chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, and the purified product was crystallized from ethyl acetate/hexane to afford 11.0 g of tert-butyl (4R,7S)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-4-methoxycarbonyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate.