Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>O1CCCC1>[CH:8](/[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[O:16])=[CH:11][CH:10]=1)=[CH:7]/[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCc1ccc(C=Cc2ccccc2)cc1)c1ccc2ncccc2c1
Solvent: C1CCOC1
Solvent: c1ccc2ncccc2c1
Product: O=C(NCc1ccc(/C=C\c2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of quinoline-6-carboxylic acid 4-phenylethenyl-benzylamide described in Preparation Example E+-5 (48 mg, 0.13 mmol), quinoline (26 mg, 0.20 mmol) and tetrahydrofuran (2 mL) was added Linear catalyst (5.0 mg), and the solution was stirred under hydrogen atmosphere at room temperature for 1 hour. The interior of the reaction system was changed to nitrogen atmosphere, then, filtration was carried out through Celite pad. The filtrate was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4), and the title compound (45 mg, 0.12 mmol, 92%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:55])([F:54])[F:56])[CH2:52][N:44]2[C:43]1=[O:57])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CC[C@H](C(F)(F)F)CN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 60 (6.3 mg, 0.023 mmol) to give a white solid (10 mg, 65% yield). Anal. Calcd. for C41H51F3N4O6S2 m/z 816.4. found: 817.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.05 (m, 10H), 6.87 (d, J=6.3 Hz, 2H), 5.33 (t, J=4.6 Hz, 1H), 5.22-5.07 (m, 2H), 5.05-4.93 (m, 1H), 4.84-4.71 (m, 1H), 4.37 (d, J=14.8 Hz, 1H), 3.69 (s, 3H), 3.33-3.10 (m, 3H), 2.92-2.51 (m, 7H), 2.48-2.20 (m, 4H), 2.12-1.92 (m, 3H), 1.93-1.76 (m, 2H), 1.77-1.19 (m, 11H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:15][C:16]1[C:21]2[NH:22][CH2:23][CH2:24][O:25][C:20]=2[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=1>>[Br:15][C:16]1[C:21]2[N:22]([C:2]3[C:3](=[O:14])[N:4]([C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:23][CH2:24][O:25][C:20]=2[CH:19]=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: COc1cc(Br)c2c(c1)OCCN2
Reactant: COC[C@H](C)n1cc(Cl)nc(Cl)c1=O
Product: COC[C@H](C)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 6.74 (d, J=3.0 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.24–5.10 (m, 1H), 4.52–3.86 (m, 4H), 3.76 (s, 3H), 3.57 (d, J=3.7 Hz, 2H), 3.35 (s, 3H), 1.41 (d, J=6.9 Hz, 3H); HRMS (ESI) m/z 444.0339 [(M+H)+, calcd for C17H20N3O4BrCl 444.0326].
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[I-].C[N+]1C=CN([C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([O:1][C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1cc(O)no1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A mixture of 3-hydroxy-5-methylisoxazole (0.30 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (25:75)) yielding the title compound (0.67 g, 96% yield) as a colourless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:46][C@@H:47](O)[CH2:48][CH:49]=[CH2:50].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:49]([CH2:48][CH:47]=[CH2:46])[CH3:50])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H](C)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O)c4)nn23)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O[C@@H](C)CC=C)c4)nn23)CC1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.19 g, 0.31 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.095 mL, 0.92 mmol, 3 equiv), and PPh3 (0.16 g, 0.62 mmol, 2 equiv) in THF (1.54 mL) was added DEAD (0.098 mL, 0.62 mmol, 2 equiv). After stirring 2 h, dilute with ether and wash with water. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-60% EtOAc in hexane) to provide the product as a white foam (0.17 g, 81%). 1H NMR (500 MHz, CDCl3) [note: 4H of piperidine not observed and are likely very broad] δ 8.16 (s, 1H), 8.08-7.99 (m, 1H), 7.61-7.56 (m, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.16 (dd, J=9.1, 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 6.92-6.82 (m, 1H), 6.08-5.97 (m, 1H), 5.74 (s, 1H), 5.42 (d, J=17.3 Hz, 1H), 5.22-5.08 (m, 2H), 5.06-4.99 (m, 2H), 4.27 (d, J=6.0 Hz, 1H), 4.03 (d, J=4.7 Hz, 2H), 3.77 (s, 3H), 2.65 (br. s., 3H), 2.45-2.35 (m, 1H), 2.28 (s, 1H), 2.06-1.95 (m, 3H), 1.79-1.69 (m, 1H), 1.38 (br. s., 3H), 1.27 (s, 9H), 1.21 (d, J=6.0 Hz, 3H). LCMS (M+1)=685.4.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[CH2:13][S:14]([CH2:17][C:18](O)=[O:19])(=[O:16])=[O:15]>C(O)(=O)C>[Cl:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[CH2:13][S:14]([C:17]1[C:18](=[O:19])[O:4][C:3]2[C:2]([CH:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:15])=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Product: O=c1oc2ccccc2cc1S(=O)(=O)Cc1ccc(Cl)cc1Cl
Yield: 86 %

Procedure:
A solution of salicylaldehyde (1 mmol) and 2-(2,4-dichlorobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate an 86% yield of the title compound; m.p. 228-229° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[C:7]=1[Br:13])(=[O:3])[CH3:2].N(OC(C)(C)C)=O.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([Br:13])=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: c1ccccc1
Reactant: CC(=O)OCc1cccc(N)c1Br
Agent: CC(C)(C)ON=O
Product: CC(=O)OCc1cccc(-c2ccccc2)c1Br
Reaction time: 48 h

Procedure:
A stirred solution of (3-amino-2-bromophenyl)methyl acetate (8.5 g, 0.035 mole) in 31.1 ml of benzene was heated at reflux. During a 40 minute period t-butyl nitrite (8.03 ml, 0.07 mole) was added to the reaction mixture. The mixture was refluxed for four hours, then held at room temperature for two days. The solvent was distilled from the reaction mixture under reduced pressure and 100 ml of n-heptane added to the residue. The solvent was removed by distillation under reduced pressure to give (2-bromo-[1,1'-biphenyl)-3-yl)methyl acetate (10.2 g) as an oil.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH:17]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])[C:18]([OH:20])=[O:19])[N:9]=1.[CH2:30](Br)[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([O:7][CH3:6])[N:9]=[C:10]([O:16][CH:17]([CH2:21][C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])[C:18]([O:20][CH2:30][CH3:31])=[O:19])[N:11]=1
Reactant: COc1cc(OC)nc(OC(Cc2c(Cl)cccc2Cl)C(=O)O)n1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(Cl)cccc1Cl)Oc1nc(OC)cc(OC)n1

Procedure:
50 ml of a N,N-dimethylformamide solution of 1.65 g of 2 (4,6-dimethoxypyrimidin-2-yl)oxy-3-(2,6-dichlorophenyl)propionic acid, 0.5 g of ethyl bromide 0.6 g of potassium carbonate was stirred at 80° C. for 2 hours under heating. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed and dried. Then, the solvent was distilled off to obtain colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH3:22])[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[N:9]=1.[Sn](Cl)Cl>Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH3:22])[C:11](=[O:23])[C:10]([CH3:25])([CH3:24])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: Cl[Sn]Cl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.5 g (0.0044 mol) of 5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 15 ml of concentrated hydrochloric acid, treated with 3.3 g of tin (II) chloride and stirred at room temperature for 15 minutes. The reaction mixture is poured into a mixture of ice and soda solution and extracted with methylene chloride. After drying and evaporating the organic phase, the residue is recrystallised from ether. There is obtained 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 190°-191°.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([C:13]2(O)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl.CO>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3c4c(cccc24)CC3)CC1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c3c(ccc(C4CCNCC4)c3c1)CC2
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate (0.44 g, 1.24 mmol) in dichloromethane (4 mL) was added triethylsilane (1.10 mL, 6.22 mmol) under nitrogen. The mixture was cooled to −30° C. then trifluoroacetic acid (0.48 mL, 6.22 mmol) added dropwise, maintaining the temperature below −25° C. After 2.5 h, the reaction mixture was allowed to warm to 0° C. and additional trifluoroacetic acid (0.48 mL, 6.22 mmol) added over 5 min. The reaction mixture was allowed to warm to room temperature and left to stir for 3 days. Ice was then added to the reaction mixture, followed by potassium hydroxide to a pH of 14, and the resultant slurry extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to yield a yellow oil. The oil was dissolved in methanol and loaded onto an SCX-2 column. The column was washed with methanol, then a 2N solution of ammonia in methanol. Concentration in vacuo of the ammonia solution yielded 4-(1,2-dihydro-5-acenaphthylenyl)piperidine as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25]C[CH2:23][CH2:22]1>>[CH2:22]([N:21]([CH2:26][CH3:25])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: O=C(c1ccc(F)cc1)N1CCCC1CN1CCCC1
Reactant: NCCCN1CCCCC1
Product: CCN(CC)CCCNc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cc1

Procedure:
(S)-[4-(3-Diethylamino-propylamino)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from (4-Fluoro-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-piperidino propylamine in a manner substantially similar to Procedure A. MS (APCI+) 399 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](OCC)(=[O:12])[C:9]([CH3:11])=O>C(O)CCC>[CH3:11][C:9]1[C:8](=[O:12])[O:4][CH2:3][C:2]([CH3:7])([CH2:5][OH:6])[N:1]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(N)(CO)CO
Solvent: CCCCO
Product: CC1=NC(C)(CO)COC1=O

Procedure:
The results presented herein above and as shown in the schematic FIGS. 1 and 2 indicate that direct condensation of 2-amino-2-methyl-1,3-propanediol (1) with ethyl pyruvate in 1-butanol at reflux, followed by vacuum distillation, gives the 2,4-dimethyl-4-hydroxymethyl-1,3-oxazolidine-2-carboxylic acid ester of 5,6-dihydro-3,5-dimethyl-5-hydroxymethyl-1,4-oxazin-2-one (2). Evidence for the structure of the latter compound (2) is derived from elemental analysis, 1H NMR, IR and UV spectra, as well as chemical behavior. As described more specifically supra, the 1H NMR spectrum of 2 in deuteriochloroform showed four methyl singlets between 1.2 and 2.3 ppm, along with two very complex patterns between 3.3 and 4.7 ppm for the four --CH2 --O groups. The sharpness of the four methyl singlets suggests that 2 is mostly one of four possible diasteroisomers. The IR spectrum showed the bands characteristic of OH and/or NH stretching at 3000-3500, a very strong band at 1735 (C= O) and a band at 1635 cm-1 (C=N). The UV spectrum of 2 in 2-propanol solvent showed a maximum at 323 nm, characteristic of the oxazinone ring.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[S:40]([CH3:43])(=[O:42])=[O:41])[N:27]2[N:26]=1)=O>>[CH3:43][S:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:33]1[N:27]2[C:28]([CH:29]=[N:30][C:25]([NH:21][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:14][CH2:13][CH:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[CH2:11][CH2:10]4)=[CH:8][C:3]=3[O:2][CH3:1])=[N:26]2)=[CH:31][CH:32]=1)(=[O:41])=[O:42]
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3S(C)(=O)=O)n2n1
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3S(C)(=O)=O)n2n1
Temperature: 190 °C

Procedure:
Following the procedure of example 532 (c), 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (0.095 g, 0.33 mmol) and 2-Methanesulfinyl-7-(2-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.17 g, 0.51 mmol) were heated in the microwave at 190° C. for 3 hours. Purification by Gilson chromatography gave [7-(2-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[2-methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a tan solid; MP: 111-112° C.; LCMS (m/e) 563 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 8.16-8.14 (d, 1H, J=8.04 Hz), 7.887.85 (t, 1H, J=7.25 Hz), 7.807.60 (t, 1H, J=7.48 Hz), 7.707.68 (d, 1H, J=7.58 Hz), 7.60 (s, 1H), 7.43-7.41 (d, 1H, J=8.45 Hz), 6.94-6.92 (q, 2H, J=5.45 Hz), 6.56 (s, 1H), 6.21-6.19 (d, 1H, J=8.80 Hz), 5.75 (s, 1H), 3.76 (s, 3H), 3.62-3.58 (m, 4H), 3.01 (s, 3H), 2.88 (s, 3H), 2.61-2.55 (t, 1H), 2.23 (t, 1H), 1.86-1.83 (d, 2H, J=11.77 Hz), 1.48-1.45 (q, 2H, J=11.36).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[NH:16][C:15]([NH2:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].N[C:20]1C([N+]([O-])=O)=CC(C)=CC=1C(O)=O>>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH2:18])[NH:14][C:13]=2[CH:12]=[C:11]([CH3:20])[CH:10]=1)=[O:8]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: Cc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Product: Cc1cc(C(=O)Nc2ncc[nH]2)c2nc(N)[nH]c2c1

Procedure:
0.25 g of 2-amino-6-methyl-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide was synthesized according to procedures described for the synthesis of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) starting from 2.5 g (12.7 mmol) of above synthesized 2-amino-5-methyl-3-nitrobenzoic acid. LCMS: 257 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.O>[C:12]([C:3]1[C:2]([NH:1][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cnc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)ethanone (0.87 g, 4.26 mmol, 1 eq.) in DCM (20 ml) were added TEA (0.65 ml, 4.69 mmol, 1.1 eq.) and ethyl 3-chloro-3-oxopropanoate (0.71 ml, 5.54 mmol, 1.3 eq.) at 0° C. The reaction mixture was stirred at RT for 3 h. Then the mixture was diluted with water (50 ml) and extracted with DCM (3×80 ml). The combined organic layers were washed with water (80 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to provide ethyl 3-(2-acetyl-5-(trifluoromethyl)pyridin-3-ylamino)-3-oxopropanoate (1.35 g, 4.24 mmol, 99%) which was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:34]=[CH:33][C:25]([O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:35])[CH:8]=1)[CH3:2].[OH-].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:35])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)OCC)cc3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of ethyl [4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenoxy]acetate (0.37 g, 0.77 mmol) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was added an aqueous solution (5 mL) of potassium hydroxide (0.26 g, 3.94 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether-hexane to give the title compound as colorless prism crystals. yield 91%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:53]1[CH:58]=[C:57]([O:59][C@H:60]([CH3:82])[CH2:61][O:62][C:63]([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[N:56]=[C:55]([S:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[C:87]([F:91])[C:86]=2[F:92])[N:54]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(C2C=CN=CC=2)(=O)=O)C=C(O[C@H](C)CO)N=1>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:92][C:86]1[C:87]([F:91])=[CH:88][CH:89]=[CH:90][C:85]=1[CH2:84][S:83][C:55]1[N:54]=[C:53]([NH:11][S:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:10])=[O:9])[CH:58]=[C:57]([O:59][C@H:60]([CH3:82])[CH2:61][O:62][C:63]([C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[N:56]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CN1CCN(S(N)(=O)=O)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)N2CCN(C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of 4-Methylpiperazine-1-sulfonamide (the product from step i) (0.64 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.55 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine ((the product of example 13 step 0.50 g) in dioxane (40 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 1 h. The reaction mixture was diluted with DCM, filtered through arbocel and the filtrate evaporated. The residue was purified by reverse phase HPLC using a TFA (0.2%)/MeCN system to give the subtitle compound as a yellow solid. Yield: 0.22 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20](NCCO)=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:26]=[N:27][N:28]=[C:11]2[CH2:10][N:9]=1.NC1C=CC2N3C=NN=C3CN=C(C3C=CC=CC=3[Cl:49])C=2C=1>C(Cl)Cl>[Cl:49][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:26]=[N:27][N:28]=[C:11]2[CH2:10][N:9]=1
Reactant: Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Solvent: ClCCl
Product: O=C=Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2

Procedure:
A solution of [6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]isocyanate is prepared as described in paragraph (a) of Example 1 from 7.0 g (22.6 mmol) of 8-amino-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine, but using methylene chloride in place of 1,2-dichloroethane.