Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[C:27]#[C:28][C:29]2([OH:39])[CH2:38][CH2:37][C:32]3([O:36][CH2:35][CH2:34][O:33]3)[CH2:31][CH2:30]2)=[CH:22][CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:28]([C:29]3([OH:39])[CH2:30][CH2:31][C:32]4([O:33][CH2:34][CH2:35][O:36]4)[CH2:37][CH2:38]3)[CH:27]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(C#CC1(O)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (457 mg, 2.62 mmol) in ethanol (4.4 mL), triethylamine (0.730 mL, 5.24 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 1-(4-chlorophenyl)-3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-2-propyn-1-one (Reference Example 18) (700 mg, 2.18 mmol) in ethanol (4.4 mL) was added dropwise, and the obtained solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (756 mg, 1.71 mmol, 79%) as an amorphous product.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([O:27]C)=[O:26])(=[O:3])[NH2:2].[Li+].[OH-]>O.C1COCC1>[C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=[O:26])(=[O:3])[NH2:2]
Reactant: COC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O

Procedure:
Methyl 10-bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (2 g) was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 2 g of methyl 2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate following triteration from water. MS (Q1) 388 (M)+. Methyl 2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (1.5 g) was saponified with LiOH in water/THF to afford quantitative yield of 2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. MS (Q1) 383 (M)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:14][CH2:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[F:33])[CH2:20][CH2:19]1)=[O:17].O>CN(C)C=O>[F:33][C:25]1[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][CH2:14][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(CCCl)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCN1CCCCC1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 41.7 %

Procedure:
Piperidine (0.081 g, 0.950 mmol) and potassium carbonate (0.380 g, 2.77 mmol) were added to a solution of 3-chlor-1-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]propan-1-one (compound of Reference Example 58; 0.250 g, 0.790 mmol) in anhydrous N,N-dimethylformamide (6 ml), and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:2) to give the title compound (0.120 g, 41%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=O)=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([NH:40][CH2:41][C:42]([NH2:44])=[O:43])[CH2:38][CH3:39]>>[NH2:44][C:42](=[O:43])[CH2:41][N:40]([CH2:37][CH2:38][CH3:39])[C:33]([C:11]1=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1)=[O:35]
Reactant: CCCNCC(N)=O
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Agent: Cl
Product: CCCN(CC(N)=O)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Step H) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 2-(propylamino)acetamide hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[NH:12]1[CH:16]=[N:15][C:14]([SH:17])=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:17][C:14]2[N:15]=[CH:16][NH:12][N:13]=2)=[C:3]([NH2:9])[CH:4]=1
Reactant: Sc1nc[nH]n1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2nc[nH]n2)c(N)c1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 1H-[1,2,4]Triazole-3-thiol (1.94 g, 19.2 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.1 g, 26%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])[CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1.FC(F)(F)C(O)=O>O1CCCC1>[NH2:30][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(C=Cc1cccnc1)NCc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)ccc1NC(=O)c1ccc(CNC(=O)C=Cc2cccnc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (15 ml) is added 0.50 g (1.78 mmol) of 4-[(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofuran (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydro ran, and then dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): δ ppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m), 6.96 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br.t), 8.78 (1H, s), 9.60 (1H, br.s), IR (KBr) cm−1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.88%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH3:32])[C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[C:25]([CH3:32])=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-cyano-3-methylpicolinic acid [S. Badiger et al. WO2011009943 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=436.5 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][C:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])([CH3:27])[CH3:26]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(C)(N)CO
Product: CC(C)(CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 39 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 2-amino-2-methyl-propan-1-ol according to the GPA affording 14.2 mg (39%) of a red powder. Rt=3.55 min.
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]([O:13]CC)=[O:12])[N:7]([CH3:16])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]([OH:13])=[O:12])[N:7]([CH3:16])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 12-L, four neck round bottom flask equipped with overhead air stirrer, positive pressure nitrogen inlet, thermocouple, and addition funnel was charged with ethyl 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate (282 g, 1.15 mol) and EtOH (4.3 L). 3M NaOH (960 mL, 2.87 mol) was added in one portion and the resulting slurry began to clarify immediately. The resulting mixture was stirred at room temperature for 2 h and yielded a turbid solution. The turbid solution was evaporated and the resulting aqueous slurry was diluted with H2O (2 L). The basic solution was acidified to pH ˜2 using concentrated HCl. The aqueous layer was extracted with dichloromethane (2×800 mL), dried over MgSO4, filtered, and evaporated to yield 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 4.11 (s, 3H), 1.41 (s, 9H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:28]([Cl:29])=[C:27](F)[N:26]=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=3)[C:24]=2[Cl:42])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][C:48]([NH:50][C@@H:51]1[CH2:56][C@H:55]([NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][NH:53][CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:28]([Cl:29])=[C:27]([N:53]3[CH2:54][C@@H:55]([NH:57][C:58]([O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:59])[CH2:56][C@@H:51]([NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:52]3)[N:26]=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=3)[C:24]=2[Cl:42])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(=O)Nc1ccc(Nc2nc(F)c(Cl)c(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2Cl)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c(Cl)c(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2Cl)cc1
Temperature: 110 °C
Yield: 42.8 %

Procedure:
4-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-3,5-dichloro-2-(4-acetylamino-phenyl-amino)-6-fluoro-pyridine (165) (0.29 g, 0.463 mmol) and cis-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (0.219 g, 0.695 mmol) were combined and suspended in NMP (3.5 mL) in a 40 mL I-Chem vial. iPr2EtN (0.926 mmol) was added and the mixture was sonicated for 2 minutes. The mixture was heated to 110° C. and within 30 minutes all of the solids had dissolved. The solution continued to shake in the Teflon septum capped vial for 5 days. LC-MS indicated nearly complete reaction at this point. The solution was diluted with EtOAc (100 mL), washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to give a brown oil which eventually solidified. Trituration of the solid with EtOAc followed by collection via filtration under reduced pressure gave the desired product (166) as a beige powder (0.183 g, 0.198 mmol, 43% yield). LC-MS (ESI): (exact mass: 921.43) m/e=922.6 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.ClC(OCC(C)C)=O.[NH3:47]>C(N(CC)CC)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH2:47])=[O:30])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2- cyclohexen-1-yl]methyl}benzoic acid (0.3 g) in a tetrahydrofuran (10 ml) were added isobutyl chloroformate (0.15 ml) and triethylamine (0.2 ml) at 0° C. under N2. After being stirred for 30 minutes, NH3 (5 ml, 4M solution in methanol) was added to the mixture. After being stirred for 30 minutes, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and lN-NaOH and the organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give and the obtained residue was purified by chromatography on silica gel to give (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}- benzamide (0.03 g).
Reaction SMILES: [CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[NH:16][C:12]4=[C:13]([CH2:14]3)[C:8](=[C:9]1[CH2:10][CH2:11]4)[CH:7]=[CH:6][NH:5][CH:4]=[CH:3]2.CN(C)C=O.C(N(C(C)C)CC)(C)C.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>O.C(OCC)(=O)C>[CH:33]1([CH2:36][N:16]2[C:12]3[CH2:11][CH2:10][C:9]4[C:2]5([CH3:1])[CH:17]([CH3:18])[CH:15]2[CH2:14][C:13]=3[C:8]=4[CH:7]=[CH:6][NH:5][CH:4]=[CH:3]5)[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CC1C2CC3=C(CCC4=C3C=CNC=CC41C)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1C2CC3=C(CCC4=C3C=CNC=CC41C)N2CC1CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a stirred solution of 2.05 g of 6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[2,3-j][3]benzazocine and 37 ml of dimethylformamide was added 2.23 ml of diisopropylethyl amine. Cyclopropylmethyl bromide (0.91 ml) was added, under nitrogen, and the reaction mixture was heated at 73°-75° C. for 3.75 hr. The mixture was cooled to room temperature and poured into ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate and ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/ethyl acetate) to afford 1.48 g (59%) of product. Recrystallization from ether gave the analytical sample, mp 151.5°-153.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1.[Li+].[OH-].Cl>C1COCC1.CO>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 7.7 mmol) in a mixture of THF (38 mL) and MeOH (15 mL) was added LiOH (2.5 M aqueous, 15 mL, 38.6 mmol). The resulting solution was stirred at room temperature for 2 h, and acidified with aqueous HCl (1N). The desired product was extracted with CH2Cl2 (4×). The combined organic layers were dried over Na2SO4 and concentrated to provide (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (2.0 g, 99%). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotomers, major reported) 4.33 (t, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.32 (s, 3H), 3.16 (t, 1H), 2.45 (m, 2H), 2.12 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[CH3:19][C:13]1([CH3:20])[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:14]1=[O:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 70 °C

Procedure:
2-Amino-4-nitrophenol (5 g), ethyl 2-bromo-2-methylpropanoate (5.77 mL, 1.2 eq.), and K2CO3 (6.7 g, 1.5 eq.) were suspended in DMF (50 ml). The reaction mixture was heated at 70° C. overnight. The mixture was then diluted with water (200 mL) and EtOAc (150 mL). The EtOAc layer was washed with water (2×150 mL) and evaporated. The residue was purified by Combiflash chromatography (EtOAc in hexanes=10-100%) to give 2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (3.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(Nc2ccccc2)c(N)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc2c(c1)nc([C@H](C)NC(=O)OC(C)(C)C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103 %

Procedure:
A mixture of 4-methyl-N1-phenylbenzene-1,2-diamine (500 mg, 2.52 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (524 mg, 2.77 mmol), HOAt (377 mg, 2.77 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (532 mg, 2.77 mmol) and 4-methylmorpholine (0.609 mL, 5.54 mmol) in anhydrous DCM (20 mL) was stirred at RT for 20 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 20 h. After cooling to RT, volatiles were removed in vacuo and the residue was dissolved in EtOAc and washed with a saturated solution of NaHCO3 (2×100 mL). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 10-60% EtOAc in cyclohexane) affording [(S)-1-(5-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (912 mg, quantitative). LCMS: RT 3.02 min [M+H-tBu]+ 352.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:16][C:17]1[C:22]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])(=[O:26])=[O:25])=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:16][C:17]1[C:22]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])(=[O:26])=[O:25])=[CH:21][C:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:19][N:18]=1
Reactant: Clc1ccc2ncnc(NC3CC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (Intermediate 20) (0.060 g, 0.272 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.141 g, 0.326 mmol), PdCl2(dppf)-CH2Cl2 Adduct (2.221 mg, 2.72 μmol) and 1 N aq. sodium bicarbonate (0.544 ml, 0.544 mmol) in dioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110° C. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(cyclopropylamino)pyrido[3,2-d]pyrimidin-6-yl) pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.070 g, 53%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 0.78-0.82 (2H, m), 1.04-1.09 (2H, m), 3.08-3.13 (1H, m), 6.95-7.02 (2H, m), 7.30 (1H, brs), 7.85-7.91 (1H, m), 8.08 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=2.0 Hz), 8.76 (1H, s), 8.81 (1H, d, J=2.0 Hz). m/z=489.2 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>CN(C)C=O>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CNCc1ccc([N+](=O)[O-])cc1
Reactant: COCCOCCCl
Solvent: CN(C)C=O
Product: COCCOCCN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
5.0 g of 4-methylaminomethyl-nitrobenzene are dissolved in 30 ml of dimethylformamide and 4.6 g of 2-(2-methoxy-ethoxy)-ethyl chloride are added. After six hours' stirring at 100° C. the solvent is removed and the residue is taken up in ethyl acetate. The organic phase is washed with water and dried over sodium sulphate. After the elimination of the solvent the residue is purified over an aluminium oxide column (activity 2-3) with toluene/ethyl acetate 5:1 as eluant.