Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CO.C(OCC)(=O)C.O1CCOCC1>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([CH2:38][N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:45][CH:44]=3)[CH:3]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5ccc(CN6CCN(C)CC6)cc5)c4)n3n2)cc(OC)c1OC
Temperature: 140 °C
Yield: 41.5 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 4-[(4-methylpiperazin-1-yl)methyl]aniline (20.9 mg, 0.102 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (11.4 mg, 0.12 mmol) was added 1,4-dioxane (1.5 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 140° C. for 60 minutes. After cooling to room temperature, diluted mixture with methanol (5 mL) and ethyl acetate (5 mL) followed by filtration over celite. Removed solvent under reduced pressure and diluted brown residue in DMSO (1.0 mL). Injected (2×0.5 mL) on an Agilent reverse phase prep LC subjected to a gradient elution using acetonitrile(0.1% Formic acid):water(0.1% Formic acid) (10:90 to 90:10). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)phenyl]-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.021 g) as a yellow solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.47 (s, 1H), 8.09 (dd, J=1.9, 1.8 Hz, 1H), 8.0-7.98 (m, 1H), 7.33 (dd, J=7.9, 7.8 Hz, 1H), 7.19 (ddd, J=7.9, 2.2, 0.8 Hz, 1H), 7.16-7.14 (m, 2H), 7.11 (s, 1H), 7.07-7.05 (m, 2H), 6.94 (m, 2H), 3.82 (s, 9H), 3.53 (s, 2H), 2.90-2.54 (m, 14H). MS m/z 595 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:32][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and phenethylarnine in DME. ES-MS m/e (%): 326 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[F:24][C:19]1[CH:18]=[C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(F)c(F)c1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(F)c(F)c2)c2ccccc2)c1
Yield: 10.2 %

Procedure:
The procedure is analogous to that described in Example 1, but 3.8 g of 2-(2-amino-N-phenylacetamido)-N-(3,4-difluorophenyl)-N-methylacetamide and 1.4 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 80 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate/cyclohexane (75-25 by volume)], collecting 20 cm3 fractions. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a cyclohexane/ethyl acetate mixture (50-50 by volume), 0.5 g of N-(3,4-difluorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 163° C is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O.CCCCCCC>[C:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1)#[N:7]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)Cn1cc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
Combined 1H-pyrazole-4-carbonitrile (0.432 g, 4.64 mmol) in acetone (9.28 mL), potassium carbonate (1.924 g, 13.92 mmol) and ethyl 2-bromoacetate (1.027 mL, 9.28 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo, diluted with EtOAc (10 mL), washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to give a residue. The residue was purified using flash column chromatography on silica gel (EtOAc in heptane, 10-50% gradient) to give a white solid. The solid was suspended in heptane and then filtered and dried to give the title compound (0.4314 g, 51.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.20 Hz, 3H) 4.17 (q, J=7.07 Hz, 2H) 5.19 (s, 2H) 8.11 (s, 1H) 8.57 (s, 1H). MS m/z [M+H]+ 180.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:28])[NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])[N:13]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:9])[C:10]([NH:11][C:12]1[N:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1)=[O:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1

Procedure:
tert-butyl-N-(1-{[4-chloro-6-(pyridine-2-amido)pyridin-2-yl]carbamoyl}ethyl)carbamate K56 (27 mg, 64 μmol) in DCM:TFA=9:1 (3 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 12 mg (58%). HPLC-MS: M+H=320; tR=1.57 min (METHOD—1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[N:13]=2)[CH:10]=1)=O.[NH2:23][C:24]([NH2:26])=[S:25]>CO>[NH2:26][C:24]1[S:25][CH:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:15])[N:13]=3)[CH:10]=2)[N:23]=1
Reactant: O=C(CBr)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: NC(N)=S
Solvent: CO
Product: Nc1nc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)cs1
Yield: 35.6 %

Procedure:
To a suspension of 60 mg of crude 6-(2-bromoacetyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 mL of methanol are added 14 mg of thiourea. The reaction mixture is heated for 45 minutes at reflux and then concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and methanol (gradient of from 100/0 to 90/10). The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 20 mg of 6-(2-aminothiazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]3[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:72])[CH:47]([C:49]4([NH:53][C:54](=[O:71])[CH:55]([NH:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:56][C:57]5([F:62])[CH2:61][CH2:60][CH2:59][CH2:58]5)[CH2:52][CH2:51][CH2:50]4)[OH:48])=[N:41]3)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1>ClCCCl>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]3[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:72])[C:47]([C:49]4([NH:53][C:54](=[O:71])[CH:55]([NH:63][C:64]([O:66][C:67]([CH3:68])([CH3:70])[CH3:69])=[O:65])[CH2:56][C:57]5([F:62])[CH2:61][CH2:60][CH2:59][CH2:58]5)[CH2:50][CH2:51][CH2:52]4)=[O:48])=[N:41]3)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(=O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.9 %

Procedure:
Dess-Martin periodinane (24 mg, 0.056 mmol) was added to a solution of alcohol 57-d (28 mg, 0.04 mmol) in anh. DCE (3 ml). The reaction mixture was stirred at room temperature for 40 min and then quenched with 10% aq. Na2S2O3 and aq. NaHCO3 (sat.). The phases were separated and the organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/iso-Hexane, 0:100-40:60) gave the title compound (21.7 mg, 79%). MS m/z 688.18 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][C:35]1[S:39][C:38]([SH:40])=[N:37][N:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58]>C1COCC1.C(OC(=O)C)C.ClCCl>[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58].[CH3:34][C:35]1[S:39][C:38]([S:40][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:37][N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1nnc(S)s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(SC2CCNCC2)s1
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry THF (30 mL) were added triphenylphosphine (2.0 g, 7.5 mmol) and 5-methyl-1,3,4-thiadiazol-2-thiol (0.79 g, 6.0 mmol). To the mixture was added diisopropyl azodicarboxylate (1.2 mL, 6.0 mmol) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethylacetate (100 mL), which was washed with saturated aqueous solution of sodium hydrogen carbonate, aqueous solution of 1N-sodium hydroxide and saturated aqueous solution of sodium chloride. The solvent was dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g, ethyl acetate-hexane 1:2) to give a crude product (1.63 g). The crude product (0.82 g) was dissolved in dichloromethane (5 mL). To the solution was added trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in water (20 mL) and washed twice with diethyl ether (20 mL). The solvent was distilled off under reduced pressure, and the residue was subjected to toluene azeotrope, and the resulting residue was vacuum-dried to give the titled compound as white solid substance (535 mg, 65%).
Reaction SMILES: [C:1]([OH:7])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:31][C:32]1[C:33]2[C:43]([O:44][CH2:45][C@H:46]3[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]3)=[CH:42][CH:41]=[CH:40][C:34]=2[NH:35][S:36](=[O:39])(=[O:38])[N:37]=1>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CN(C=O)C>[NH2:31][C:32]1[C:33]2[C:43]([O:44][CH2:45][C@H:46]3[CH2:51][CH2:50][CH2:49][N:48]([C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:47]3)=[CH:42][CH:41]=[CH:40][C:34]=2[NH:35][S:36](=[O:38])(=[O:39])[N:37]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: CC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Temperature: 130 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Pivalic acid (71 mg, 0.692 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (117 mg, 0.865 mmol), and 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide HCl (166 mg, 10.8 mmol) were placed into a 20 mL microwave flask and diluted with anhydrous CAN (12 mL) then a solution of(S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a, 200 mg, 0.577 mmol) and TEA (320 uL, 2.30 mmol) in DMF (2 mL) was added. The mixture was heated with stirring in the microwave at 130° C. for 1 hour then cooled to room temperature, transferred to 250 mL round bottom flask and concentrated via rotary evaporation. The residue was purified via preparative RP HPLC (10 to 90% ACN in water). The pure fractions were collected and dried then diluted with water (6 mL) and NaHCO3 (100 mg) was added and the solution heated to 90° C. for 15 minutes until the entire compound dissolved. The solution was then cooled to 0° C. and neutralized with 1N HCl solution. The precipitate was collected and dried to provide the title compound (110 mg, 48%). 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.15 (s, 9H), 1.35 (m, 2H), 1.68 (br s, 1H), 1.85 (br s, 1H), 2.05 (br s, 1H), 2.83 (br s, 2H), 2.16 (br s, 2H), 4.06 (d, J=8 Hz, 2H), 4.12 (d, J=12 Hz, 1H), 4.20 (d, J=16 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.78 (s, 1H), 8.37 (s, 1H), 10.93 (s, 1H). M+H=395.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:3]2[C:4](=[O:6])[N:35]3[N:34]=[C:33]([C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:31][C:30]3=[N:1][C:2]=2[CH:12]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CCOC(=O)c1ccc(NC(C)=O)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc3cc(NC(C)=O)ccc3c(=O)n2n1

Procedure:
A solution of ethyl 2-amino-4-(acetylamino)benzoate (4.03 g, 18.13 mmol, Example 4, Step A), p-toluenesulfonic acid, monohydrate (0.5 g, 2.63 mmol) and methyl 6-chloro-3-pyridazinecarboxylate [3.13 g, 18.14 mmol, prepared according to the procedure of Barlin, G. B. and Yap, C. Y. (Aust. J. Chem. 1977, 30, 2319-2322)] in 500 mL of toluene was refluxed under Dean-Stark conditions for 12 h. The mixture was concentrated, dissolved into chloroform, washed with saturated sodium bicarbonate solution, dried (MgSO4), filtered and concentrated. Medium pressure chromatography (silica gel, 5% methanol in chloroform) afforded methyl 7-acetylamino-10-oxo-10H-pyridazino[6,1-b]-quinazoline-2-carboxylate as a yellow solid, mp 281°-285° C., dec.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8](OCC)=[O:9])[C:4](=[O:13])[CH2:3]1.[NH3:14]>CC(C)=O>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:14])=[O:9])[C:4](=[O:13])[CH2:3]1
Reactant: CCOC(=O)CN1CC(O)CC1=O
Reactant: N
Solvent: CC(C)=O
Product: NC(=O)CN1CC(O)CC1=O
Temperature: 25 °C

Procedure:
A solution of 7.1 g ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate obtained in Example 12, in 7.1 ml ammonia solution (d25 =0.90) is stirred at ambient temperature for 15 h. It is then diluted with 140 ml acetone and the mixture is stirred at ambient temperature until the gum that precipitates solidifies into white crystals. On filtering in vacuo and drying, 4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained, m.p. 160°-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.O.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)nc(Cl)c1N
Temperature: 95 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridin-4-amine in ethanol (150 mL) was added iron powder (14.3 g, 0.255 mol), water (46 mL), and then concentrated HCl (28 mL). The reaction mixture was then stirred at 95° C. for 16 hours, cooled to room temperature, and neutralized. The precipitates were collected by filtration and dried in vacuo. The crude product was then treated with water (200 mL) and extracted with EtOAc (3×200 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 7.85 g of the title compound (86.5% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(O)c(C(=O)/C=C/c2ccccn2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(C(=O)CCc2ccccn2)cc1C
Yield: 49.2 %

Procedure:
In a 250 ml round-bottom flask, (E)-1-(2-hydroxy-4,5-dimethylphenyl)-3-(pyridine-2-yl)prop-2-en-1-one (1.17 g, 4.62 mmol) and 0.18 g of 10% Pd/C were mixed together in wet EtOAc. Hydrogenation was conducted at atmospheric pressure, then the catalyst was filtered off. The crude product was purified by chromatography on silica gel (20% EtOAc/hexane) to provide 0.58 g (47.7%) of final compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].[C:32]([Si:36]([CH3:56])([CH3:55])[O:37][CH2:38]/[C:39](/[CH3:54])=[CH:40]\[Sn](CCCC)(CCCC)CCCC)([CH3:35])([CH3:34])[CH3:33].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.CS(C)=O.C(OCC)(=O)C.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]>[Si:36]([O:37][CH2:38]/[C:39](/[CH3:54])=[CH:40]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10])([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:55])[CH3:56]
Reactant: CCCC[Sn](/C=C(/C)CO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C(/C)CO[Si](C)(C)C(C)(C)C)ccc2c1OCC1CC21
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxy-carbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 65, 0.257 g), tert-butyl-dimethyl-((Z)-2-methyl-3-tributylstannanylallyloxy)silane (0.475 g), tris(dibenzylideneacetone)dipalladium(0) (0.023 g) and tri-tert-butylphosphonium tetrafluoroborate (0.015 g) in dioxane (8 mL) and DMSO (0.8 mL) was stirred and heated at 90° C. under nitrogen for 1 hour. Further tris(dibenzylideneacetone)dipalladium(0) (0.023 g) and tri-tert-butylphosphonium tetrafluoroborate (0.015 g) were added and heating was continued for a further 40 minutes. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give methyl (1aRS,7bSR)-5-(N-{2[(Z)-3-(tert-butyldimethylsilanyloxy)-2-methylprop-1-enyl]-4-fluorobenzenesulfonyl]-N-methoxycarbonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.231 g) as a colourless gum.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][C:6]([NH2:9])=[N:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[N:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:9]=[C:6]3[CH2:7][CH2:8][O:2][CH2:3][CH2:4][N:5]3[C:24](=[O:25])[CH:23]=2)=[N:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: NC1=NCCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To a suspension of 25.00 g (165.99 mmol) of 2,3,6,7-tetrahydro-[1,4]oxazepin-5-ylamine monohydrochloride (synthesis as described in WO97/16430 and Bioorganic & Medicinal Chemistry Letters (2004), 14(23), 5907-5911) in 550 mL of ethanol was added 25.23 g (182.59 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 35.45 g (182.59 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 4 hours. The cooled solution was evaporated to remove solvent. The mixture was dissolved with water and diethyl ether. After stirring, the resulting solid was filtered, washed with water and diethyl ether to afford 21.7 g (53%) of the desired compound as a powder.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](CC2CCC(F)(F)CC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCC(F)(F)CC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
Trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (300 mg, 0.77 mmol) (from example 89, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.227 mL, 0.77 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.047 mL, 0.77 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (267 mg, 97%) as a slightly yellow solid. MS m/z 357 (M−H)−