Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=3)[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:6]2[N:5]=1)=O.[NH2:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([CH3:38])([CH3:37])[C:32](=[O:36])[NH:33]2)=[CH:29][CH:28]=1>>[CH3:37][C:31]1([CH3:38])[C:30]2[C:34](=[CH:35][C:27]([NH:26][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=5)[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:6]4[N:5]=3)=[CH:28][CH:29]=2)[NH:33][C:32]1=[O:36]
Reactant: CN(Cc1cccc(-c2ccc3cnc(S(C)=O)nn23)c1)S(C)(=O)=O
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Product: CN(Cc1cccc(-c2ccc3cnc(Nc4ccc5c(c4)NC(=O)C5(C)C)nn23)c1)S(C)(=O)=O

Procedure:
N-{3-[2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzyl}-N-methyl-methanesulfonamide was prepared from N-[3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-N-methyl-methanesulfonamide and 6-amino-3,3-dimethyl-1,3-dihydro-indol-2-one in an analogous manner to Example 1049. Product isolated as a yellow foam (23 mg, 19%). LCMS (m/e) 491 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 8.09 (s, 1H), 7.56-7.52 (m, 1H), 7.52-7.46 (m, 1H), 7.44 (s, 1H), 7.35 (d, 1H, J=7.6 Hz), 7.10 (d, 1H, J=8.0 Hz), 7.05-6.98 (m, 2H), 6.93 (s, 1H), 6.86 (d, 1H, J=4.8 Hz), 4.41 (s, 2H), 2.90 (s, 3H), 2.83 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:6][N:5]([CH3:7])[C:3](=[O:4])[CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNS(C)(=O)=O

Procedure:
To a cold (0° C.) solution of 2-amino-N,N-dimethylacetamide (1.62 g, 10 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (50 mL), methanesulfonyl chloride (0.85 mL, 11 mmol) was added over a period of 5 minutes. The resultant mixture was stirred at room temperature for overnight. The product mixture was diluted with dichloromethane and washed with sat. aq. sodium bicarbonate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title acetamide as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[N:21]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][N:23]=[CH:22]1>>[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:20][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([CH2:13][N:14]5[CH2:18][CH2:17][CH2:16][CH:15]5[CH3:19])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:31])=[CH:33][CH:34]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-imidazol-1-yl-benzoic acid. MS: 444.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Yield: 64 %

Procedure:
A mixture of 6-nitroindazole (2 g, 12 mmol) and potassium carbonate (5.1 g 37 mmol) in DMF (40 mL) for 30 minutes, followed by the addition of 2-(dimethylamino)ethylchloride hydrochloride (2.65 g 18.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.8 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) ppm 2.16 (s, 6H), 2.73 (t, J=6.44, 2H), 4.66 (t, J=6.44, 2H), 7.94 (m, 1H), 8.00 (m, 1H), 8.31 (m, 1H), 8.79 (m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[CH2:14][C:15](N)=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][Mg]I.[Mg].CI.S(=O)(=O)(O)O>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[CH3:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Mg]I
Reactant: CC(CC(N)=O)c1ccc(C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CI
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)CC(C)c1ccc(C2CCCCC2)cc1
Temperature: 0 °C

Procedure:
A solution of 24.54 gm (0.1 mol) of 3-(4-cyclohexylphenyl)-butyramide in 750 ml of dry methylene chloride was added dropwise within one hour to a methyl magnesium iodide solution, prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in a total of 400 ml of anhydrous ether, and, to complete the reaction, the resulting mixture was refluxed for 6 hours. The cooled mixture was then stirred into a mixture of 2 kg of ice and 100 ml of concentrated sulfuric acid. The organic phase was separated and washed twice with water, then with a saturated aqueous sodium bicarbonate solution and finally once more with water, then dried over anhydrous magnesium sulfate and concentrated by evaporation in vacuo. The residue was chroomatographically purified on 800 gm of silicagel, using benzene as the eluant, and the evaporated eluates were finally distilled in vacuo. 19.8 gm (81% of theory) of colorless oil, b.p. 104°-106°C at 0.05 mm Hg were obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[O:8]1[C:4]2[CH:3]=[C:2]([C:18]3([OH:21])[CH2:19][CH2:20][C:15]4([O:14][CH2:13][CH2:12][O:11]4)[CH2:16][CH2:17]3)[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCC2
Product: OC1(c2ccc3c(c2)OCC3)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 6-bromo-2,3-dihydro-benzofuran (Milestone) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH:5]([C:8](O)=O)[CH2:4][CH2:3]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH2:28][C:29]1[C:30]([OH:40])=[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])[C:32]([Cl:35])=[CH:33][CH:34]=1.C[N:42]([CH:44]=[O:45])C>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:44]([NH:42][CH:2]2[CH2:3][CH2:4][CH:5]([CH3:8])[CH2:6][CH2:7]2)=[O:45])=[C:30]([OH:40])[C:31]=1[S:36](=[O:38])(=[O:37])[NH2:39]
Reactant: CC1CCC(C(=O)O)CC1
Reactant: CN(C)C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CC1CCC(NC(=O)Nc2ccc(Cl)c(S(N)(=O)=O)c2O)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-Methyl-cyclohexanecarboxylic acid (0.141 mL) in DMF (0.5 mL) was added DPPA (0.215 mL) and TEA (0.139 mL) and the reaction heated at 80° C. After 18 hrs, 3-Amino-6-chloro-2-hydroxy-benzenesulfonamide (0.150 g) was added and the reaction heated at 80° C. After 18 hrs, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and concentraed under reduced pressure. The crude residue was purified via HPLC to give 15 mg of N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-N′-(4-methyl-cyclohexyl) urea. LC-MS (m/z) 347 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][OH:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][O:12][C:17](=[O:20])[CH2:18][CH3:19])[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CCC(=O)Cl
Solvent: CC(=O)Cl
Product: CCC(=O)OC[C@@H](C)NC(=O)OC(C)(C)C

Procedure:
Following the procedure of example 47A, but replacing N-(tert-butoxycarbonyl)L-alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[CH2:11]([O:13][C:14](=O)[CH:15]=[C:16](OCC)[O:17]CC)[CH3:12]>C(O)(=O)C>[CH2:11]([O:13][C:14]1[CH2:15][C:16](=[O:17])[NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[N:1]=1)[CH3:12]
Reactant: CCOC(=O)C=C(OCC)OCC
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CC(=O)O
Product: CCOC1=Nc2cc(F)c(F)cc2NC(=O)C1
Temperature: 140 °C
Yield: 80.7 %

Procedure:
To a solution of 1,2-diamino-4,5-difluorobenzene (4.0 g, 27.75 mmol) in xylenes (50 mL) at 140° C. was added acetic acid (200 μL) followed by a solution of 3,3-diethoxyacrylic acid ethyl ester (5.22 g, 27.75 mmol) in xylenes (25 mL) over 1 hour. The reaction was heated at 140° C. for 2 hours, was cooled to room temperature, and was concentrated. The residue was triturated in hexanes to provide 5.38 g of 4-ethoxy-7,8-difluoro-1,3-dihydro-benzo[b][1,4]diazepin-2-one. 1H NMR (CDCl3) δ 7.05 (q, 1H), 6.87 (q, 1H), 4.29 (q, 2H), 3.18 (s, 2H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.O[CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>>[ClH:1].[CH3:48][N:47]([CH3:49])[C:45]([CH2:44][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:46]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN(C)C(=O)CO
Product: COc1cc(C(=O)OCC(=O)N(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: Cl

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-hydroxy-N,N-dimethylacetamide to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid dimethylcarbamoylmethyl ester, hydrochloride. MS (ES+) m/z calcd. for C35H37Cl2F2N4O5: [(M+H)+]: 703. found: 703.
Reaction SMILES: Cl.[N:2]1([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:2]1([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([O:11][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ccc(C(C(=O)O)N2CCCCC2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(C(=O)O[C@H]2CN3CCC2CC3)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
2-(Piperidin-1-yl)-2-p-tolylacetic acid hydrochloride (242 mg, 0.90 mmol), DCC (370 mg, 1.79 mmol) and HOBT (275 mg, 1.79 mmol) were dissolved in dry THF (10 ml). (R)-quinuclidin-3-ol (342 mg, 2.69 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was recovered, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(piperidin-1-yl)-2-p-tolylacetate (169 mg, 55% yield) as a colourless oil.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH2:17])[CH3:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCOCC>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:17][C:34]2=[O:36])[CH3:11])=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NCCCC(N)c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCCC(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A stirred solution of N1—((1S)-1-(4-bromophenyl)ethyl)-4-phenylbutane-1,4-diamine dihydrochloride (19.5 mg, 0.046 mmol) and i-Pr2NEt (0.10 mL, 0.56 mmol) in CH2Cl2 (8 mL) was cooled in an ice bath and solid triphosgene (4.6 mg, 0.015 mmol) was added. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over MgSO4. Removal of the solvent left a residue (17.5 mg) which was purified by preparative HPLC to afford 1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (1.4 mg, 8%). LC-MS (3 min) tR=2.05 min, m/z=375, 373.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].Cl[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(#N)C.[CH2:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1)[CH2:15][CH2:16][CH3:17]>O>[CH2:9]([O:8][C:6]([NH:3][C:2]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26])=[S:1])=[O:7])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: N#C[S-]
Reactant: CCCCc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCc1ccc(NC(=S)NC(=O)OCC)c([N+](=O)[O-])c1
Temperature: 15 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Dry potassium thiocyanate (18.5 g), ethyl chloroformate (15.6 g) and dry acetonitrile (65 ml) were mixed with stirring at laboratory temperature and stirring was continued for 1 hour at 45°-55° C. The mixture was then cooled in an ice bath to 15° C. and 4-n-butyl-2-nitroaniline (19.0 g) was added in portions with stirring during 15 minutes, the temperature of the stirred reaction mixture being maintained between 15 and 18° C. during the addition. When the addition was complete the mixture was stirred at 15° C. for 2 hours, poured into water (1 litre), and the yellow solid which separated was filtered off and washed with water. This crude product was recrystallised from cyclohexane to give 1-ethoxycarbonyl-3-(4-n-butyl-2-nitrophenyl)thiourea (26.9 g), m.p. 121°-123° C.
Reaction SMILES: BrC1C=CC2C3N(C=C(C4N(C(C)C)N=C(C)N=4)N=3)CCOC=2C=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1.[NH2:35][OH:36]>>[Br:25][C:26]1[CH:33]=[CH:32][C:29]([C:30](=[NH:31])[NH:35][OH:36])=[C:28]([F:34])[CH:27]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NO
Agent: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: N=C(NO)c1ccc(Br)cc1F

Procedure:
Scheme 10 shows the synthesis of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2-fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3-dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III.
Reaction SMILES: [NH:1]([C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7](O)=[O:8])=[O:4].[OH:29]N1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:52][C@H:53]([C:61]([NH:63][CH2:64][C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CN1CCOCC1>CN(C=O)C>[NH:1]([C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:52][C@H:53]([C:61]([NH:63][CH2:64][C:65]([O:67][C:68]([C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:29])=[O:66])=[O:62])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:8])=[O:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC(=O)c1ccccc1

Procedure:
To 10 ml of dry DMF were added 1.54 g of Trt-Gly-Gly, 0.52 g of N-hydroxysuccinimide and 0.93 g of DCC, followed by effecting a reaction at 4° C. for 3 hours, to thereby obtain a reaction mixture. To the obtained reaction mixture was added a DMF solution containing 2.0 g of Phe-Gly-OBn para-toluenesulfonate synthesized in item (1) and 0.41 g of N-methylmorpholine, which are dissolved in 10 ml of DMF, followed by effecting a reaction at 4° C. for 15 hours, to thereby obtain a reaction mixture. A precipitate contained in the obtained reaction mixture was removed and the resultant solution was evaporated to dryness, to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography (silica gel: Art No. 9365, Silica gel 60, 200-400 mesh, manufactured and sold by E. Merck, Darmstadt, Germany, eluent: chloroform/methanol=20/1), to thereby obtain 1.5 g of Trt-Gly-Gly-Phe-Gly-OBz.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:9][N:8]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[CH2:36][C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)[C@H](Cc2cccs2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid methyl ester (8.73 mmol; 2.7 g) in DMF (20 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (9.58 mmol; 2.60 g), N,N-diisopropyl-N-ethylamine (17.46 mmol; 3.1 mL) and HBTU (10.48 mmol; 3.97 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added and the resulting solution was washed with a 1N hydrochloric acid solution (2×50 mL) and brine (50 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 60% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid methyl ester after evaporation. MS (ESI) m/z 565.36 [M+H]+.
Reaction SMILES: [N:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[OH:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1>[CH3:23][N:24]([CH3:28])[C:25]([O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:8]=[CH:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:26]
Reactant: Oc1cnccc1N=CN1CCOCC1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCOCC1

Procedure:
A mixture prepared from 4-[[(4-morpholinyl)methylene]amino]-3-pyridinol (3.04 g), triethylamine (3.19 mL), dimethylcarbamyl chloride (2.04 mL) and tetrahydrofuran (121 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. Recrystallization from ethyl acetate (50 mL) and drying under high vacuum and refluxing acetone overnight yielded 3.04 g of fluffy needles, m.p. 127°-129° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:34]=[N:33][C:32]3[C:31]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[N:30][C:29]([C:41]4[CH:42]=[N:43][C:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[N:45][CH:46]=4)=[N:28][C:27]=3[CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[O:17]>CN(C=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:34]=[N:33][C:32]4[C:31]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[N:30][C:29]([C:41]5[CH:42]=[N:43][C:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[N:45][CH:46]=5)=[N:28][C:27]=4[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:17])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)CCl)c4)cc3n2)cn1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)CN5CCC(O)CC5)c4)cc3n2)cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a 25 mL round bottom flask, 4-hydroxy piperidine (0.021 g, 0.00021 mol) and DMF (1.5 mL) were added and then cooled to 0-10° C. To the same reaction flask, potassium carbonate (0.058 g, 0.00042 mol) was added and the reaction mixture was stirred at 0-10° C. for 30 minutes. To the same flask, a solution of tert-butyl (5-(7-(3-(2-chloroacetamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.08 g, 0.00014 mol) in DMF (1 mL) was added and then stirred at room temperature for 12 hours. The reaction was quenched with water to provide the precipitate. The precipitate was collected by filtration to provide the title compound (0.078 g, 88%). The compound was used in the next step without purification. 1H NMR (300 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.84 (s, 1H), 9.49 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.38 (s, J=2.1 Hz, 1H), 8.21 (br s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 4.63 (d, J=3.9 Hz, 1H), 4.58 (br s, 4H), 3.84 (s, 4H), 3.51-3.49 (m, 1H), 3.28 (s, 2H), 3.13-2.75 (m, 2H), 2.29 (t, J=8.7 Hz, 2H), 1.78 (d, J=9.3 Hz, 2H), 1.58 (d, J=9.3 Hz, 2H), 1.49 (s, 9H): LCMS (ESI): Calculated. 641.3, Observed mass [M+H]+: 642.2, (RT=0.22 min).