Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:16][CH:15]=[C:14]([Cl:34])[N:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1.C(N(CC)CC)C.[F:42][C:43]1([F:60])[C:47]2[N:48]([CH2:55][C:56](O)=[O:57])[N:49]=[C:50]([C:51](F)([F:53])[F:52])[C:46]=2[C@H:45]2[CH2:59][C@@H:44]12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:34][C:14]1[N:13]=[C:12]([C@@H:2]([NH:1][C:56](=[O:57])[CH2:55][N:48]2[C:47]3[C:43]([F:42])([F:60])[C@@H:44]4[CH2:59][C@@H:45]4[C:46]=3[C:50]([CH:51]([F:53])[F:52])=[N:49]2)[CH2:3][C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=2)[C:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:33])=[C:22]3[C:26]=2[N:25]([CH3:27])[N:24]=[C:23]3[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:16][CH:15]=1
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of crude (S)—N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-chloropyridin-3-yl)-4-chloro-1-methyl-1H-indazol-3-yl)methanesulfonamide (60A, 400 mg, 0.76 mmol) in DMA (6 mL) was added triethylamine (0.32 mL, 2.28 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (30J, 0.61 mmol), then HATU (173.4 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then additional HATU (86.7 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for an additional 15 minutes. Upon completion, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound (60B). MS (m/z) 790.05 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH2:4][C:3]1([CH3:16])[CH3:15].[CH3:17][NH:18][CH3:19]>O>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][N:18]([CH3:19])[CH3:17])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1O
Reactant: CNC
Solvent: O
Product: CN(C)CC(O)COC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 10.0 g (0.044 mol) of 1-oxyl-2,2,6,6-tetramethyl-4-glycidyloxypiperidine and 10 mL of 40% (ca. 0.091 mol) of dimethylamine (w/w) is dissolved in 100 mL of water and then stirred for 16 hours at ambient temperature. Water is then removed by vacuum distillation to leave 10 g of the title compound as a red oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27].[F:30][CH:31]([F:63])[O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH3:42])[N:37]=[C:36]2[C:43]1[N:44]=[C:45]2[C:51]([C:52](O)=[O:53])=[CH:50][N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[C:46]2=[N:47][CH:48]=1>CN(C=O)C>[C:26]([NH:29][C:52]([C:51]1[C:45]2[C:46](=[N:47][CH:48]=[C:43]([C:36]3[C:35]4[C:39](=[CH:40][CH:41]=[C:33]([O:32][CH:31]([F:30])[F:63])[CH:34]=4)[N:38]([CH3:42])[N:37]=3)[N:44]=2)[N:49]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:50]=1)=[O:53])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)N
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and 2-methylpropan-2-amine (17.9 mg, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight. TLC and LCMS showed incomplete reaction, added 2-methylpropan-2-amine (17.9 mg, 245 μmol) and HATU (28.0 mg, 73.5 μmol.20) then the reaction continued at 25° C. for 3 h. Solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield N-tert-butyl-2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33.4 mg, 61.3 μmol, 100%) as an off-white solid. 1H NMR (CDCl3) δ: 9.21 (s, 1H), 8.35 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.44-7.53 (m, 1H), 7.30-7.38 (m, 1H), 7.27 (s, 2H), 6.39 (t, J=74.0 Hz, 1H), 5.72 (s, 2H), 4.21 (s, 3H), 3.50-3.65 (m, 2H), 1.61 (s, 9H), 0.86-1.07 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]([O:31]C)=O)=[N:23][N:22]4[C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:40]>CO.C1COCC1>[C:29]([C:24]1[CH:25]=[C:26]([O:27][CH3:28])[C:21]2[N:22]([C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:9]4([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10]4)=[CH:14][CH:15]=3)[N:20]=2)[N:23]=1)(=[O:31])[NH2:40]
Reactant: N
Reactant: COC(=O)c1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(N)=O)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Yield: 63 %

Procedure:
A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-9 (0.20 g, 0.38 mmol) in a solution of ammonia in MeOH (7 N, 15 mL) and THF (1 mL) was irradiated in a microwave apparatus at 130° C. for 90 min. The solids were collected by filtration to give tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 63%):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C1C(=O)N([Cl:18])C(=O)C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][C:6]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(Br)co1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(Cl)o1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of methyl 4-bromo-2-furancarboxylate (1.4 g, 6.83 mmol) and NCS (0.912 g, 6.83 mmol) in N,N-dimethylformamide (13.7 ml) was stirred in a sealed tube for 1 h at 100° C. After 1 h, the solution was partitioned between DCM-H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (2-10% EtOAc in hexanes) affording methyl 4-bromo-5-chloro-2-furancarboxylate (1.348 g, 5.12 mmol, 75% yield) as a white solid: LCMS (ES) m/e 238, 240, 242 (M, M+2, M+4)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH:18][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[CH:11]=1)(C(C)(C)C)(C)C.N1C=CC=CC=1.F>C1COCC1>[CH2:16]([C:14]1[N:13]=[C:12]([NH:18][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=1)[CH3:17]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(Nc2ncc(C#N)s2)n1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1cc(CO)cc(Nc2ncc(C#N)s2)n1
Reaction time: 1.5 h

Procedure:
2-{[4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (12-2) (0.225 g, 0.60 mmol) was dissolved in 2 mL THF. Hydrogen fluoride-pyridine (Aldrich, HF ˜70%, pyridine ˜30%) (0.060 mL) was added. After 1.5 hours, additional hydrogen fluoride-pyridine (0.50 mL) was added. After 2.5 hours the reaction was concentrated to remove THF and the residue was diluted with 1M aqueous K2CO3. The resulting precipitate was filtered and washed with water to afford the desired compound 12-3 as a yellow solid. 1H NMR (DMSO-d6) δ 12.19 (s, 1H), 8.26 (s, 1H), 6.96 (s, 1H), 6.86 (s, 1H), 4.51 (bs, 2H), 2.79 (q, 2H, J=7.63 Hz), 1.32 (t, 3H, J=7.63 Hz). [M+H]+=261.0816.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[C:41]([C:53]([O:55][CH3:56])=[O:54])[C:42]3[NH:43][C:44]4[CH:45]=[C:46]([OH:52])[CH:47]=[CH:48][C:49]=4[C:50]=3[N:51]=2)=[CH:35][CH:34]=1.[O:57]1[CH2:62][CH2:61][N:60]([CH2:63][CH2:64][CH2:65]O)[CH2:59][CH2:58]1>C1COCC1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[C:41]([C:53]([O:55][CH3:56])=[O:54])[C:42]3[NH:43][C:44]4[CH:45]=[C:46]([O:52][CH2:65][CH2:64][CH2:63][N:60]5[CH2:61][CH2:62][O:57][CH2:58][CH2:59]5)[CH:47]=[CH:48][C:49]=4[C:50]=3[N:51]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(O)ccc12
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCCCN3CCOCC3)ccc12
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Diethyl azodicarboxylate (90 μL, 0.57 mmol) was added to a solution of triphenylphosphine (149 mg, 0.567 mmol), methyl 2-(4-chlorophenyl)-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (100 mg, 0.283 mmol) and 3-morpholinopropan-1-ol (78 μL, 0.57 mmol) in dry THF (1.4 mL) at RT under nitrogen. After 1 hr, the reaction was quenched with a little water and the product was captured on an SCX cartridge, washed with MeOH and DCM, and then released with 2 N NH3 in MeOH. Radial chromatography (step gradient elution with DCM containing 0 to 1% MeOH) afforded impure methyl 2-(4-chlorophenyl)-7-(3-morpholinopropoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (75 mg) as a yellow solid. MS (ESI) m/z 480.0 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)=[O:4].[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH:23]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][N:7]=4)[CH:22]=[CH:21][C:15]=3[CH2:16][CH2:17]2)[CH2:26][CH2:25][CH2:24]1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide (D40) (1.04 g, 3.5 mmol) in dichloromethane (12 ml) containing acetic acid (240 μL) at 0° C. was treated dropwise with cyclobutanone (400 μL, 5.3 mmol) and then stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and treated portionwise with sodium triacetoxyborohydride (1.11 g, 5.3 mmol) and stirred at room temperature for 16 hours. The solution was carefully basified with 2N sodium hydroxide, stirred for 30 minutes and then extracted with dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E121); MS (ES+) m/e 352 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH2:14]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH:24]2[C:29](=O)[CH2:28][CH2:27][N:26]([CH3:31])[CH2:25]2)=[CH:18][C:17]=1[O:32][CH3:33])[CH3:15]>O1CCCC1>[CH2:14]([C:16]1[C:17]([O:32][CH3:33])=[CH:18][C:19]([CH:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]/[C:29]/2=[CH:5]\[C:3]([O:2][CH3:1])=[O:4])=[CH:20][C:21]=1[O:22][CH3:23])[CH3:15]
Reactant: CCc1c(OC)cc(C2CN(C)CCC2=O)cc1OC
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(OC)cc(C2CN(C)CC/C2=C\C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A solution of 39 ml (262.4 mmol) of trimethyl phosphonoacetate in 450 ml of tetrahydrofuran was added dropwise at 0° to a suspension of 9.54 g (238.5 mmol) of sodium hydride (55% in mineral oil) in 450 ml of tetrahydrofuran and the mixture was stirred for 30 minutes. Subsequently, the white suspension was treated with a solution of 33.15 g (119.5 mmol) of 3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-one in 450 ml of tetrahydrofuran and the mixture was stirred at 50° for 2 hours. After cooling to room temperature the mixture was poured on to 500 ml of ice-water and extracted three times with 400 ml of diethyl ether. The organic phases were washed with 400 ml of water and 400 ml of saturated sodium chloride solution, dried (Na2SO4), filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 19:1) and recrystalization from hexane yielded 36.33 g (91%) of methyl (E)-[3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-ylidene]acetate as pale yellow crystals of m.p. 110-112°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCN(C(=O)COc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 80 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 80% yield. LCMS for C28H28ClN8O4 (M+H)+: m/z=575.0.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:12])[C@@H:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].ClC(Cl)(Cl)C(=N)O[CH:17]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCCl>[Br:30][C:27]1[CH:26]=[CH:25][C:24]([CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:11][C@@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:12])=[CH:29][CH:28]=1
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Reactant: N=C(OC(c1ccccc1)c1ccc(Br)cc1)C(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)cc1)C(=O)NCC#N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 626.4 %

Procedure:
(2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from example 67 step 1 (22.5 g, 0.132 mol) and (1R)-(-1-10-camphorsulfonic acid (2.85 g, 0.012 mol, 0.1 eg) were added to 1,2-dichloroethane (135 mL) and the suspension was heated to 50° C. (4-bromophenyl)(phenyl)methyl 2,2,2-trichloroethanimidoate (50 g, 0.123 mol, 0.93 eg) was added portionwise over 15 min. then reaction mixture was stirred at 50° C. for 10 min. The reaction was repeated with 2×50 g and 1×69 g of (4-bromophenyl)(phenyl)methyl 2,2,2 trichloroethanimidoate, using same proportions of other reagents. All the batches were combined and evaporated to give a dark red oil (320 g). The latter was dissolved in toluene (600 mL); insoluble material was filtered off and the filtrate was charged on a chromatography column, eluted with 5% EtOAc/toluene to give the title compound.
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[C:7]3[O:6][C:5]([NH2:4])=[N:9][C:8]=3[C:10]([O:21][CH3:22])=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3ccc(F)cc3)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Temperature: 100 °C
Yield: 41.6 %

Procedure:
To a stirred solution of 2.80 g (8.85 mmol) [7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-carbamic acid methyl ester in 100 ml dioxane and 30 ml ethylene glycol was added 100 ml of a 5 N aq. sodium hydroxide solution, and the mixture was heated at 100° C. for 16 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Trituration in ether afforded 0.95 g (42%) 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine as an off-white solid. ES-MS m/e (%): 259 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:15])=[O:6])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(Cl)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70° C. and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10% aqueous K2CO3 (2×150 mL) dried with MgSO4, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5].[OH-].[Na+].[CH2:22]=O>CCO>[Br:19][C:16]1[CH:17]=[N:18][C:2]2[NH:1][CH2:22][N:6]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[C:4](=[O:5])[C:3]=2[CH:15]=1
Reactant: Nc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc(Br)cnc2NCN1Cc1ccc(F)cc1
Yield: 87 %

Procedure:
To a solution of 2-amino-5-bromo-N-(4-fluorobenzyl)nicotinamide (200 mg, 0.62 mmol) and NaOH (50 mg, 1.23 mmol) in 10 mL of EtOH was added HCHO (1 mL, 37% in water) and then the mixture was heated at reflux for 30 minutes. After being concentrated in vacuo, the residue was suspended in water and extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product of 6-bromo-3-(4-fluorobenzyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (180 mg, yield: 87%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.28˜8.32 (m, 2H), 7.26˜7.31 (m, 2H), 7.02 (t, J=8.4 Hz, 2H), 5.01 (s, 2H), 4.68 (d, J=2.4 Hz, 2H). MS (M+H)+: 336/338.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(O)(=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([NH:17][CH2:16][CH2:15][NH2:18])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(=O)c1ccc(-n2cnnn2)cc1
Reactant: NCCN
Solvent: CC(=O)O
Product: CC(NCCN)c1ccc(-n2cnnn2)cc1

Procedure:
By using 1-[4-(1H-tetrazol-1-yl)phenyl]ethanone (250 mg), ethylenediamine (400 μl) and acetic acid (700 μl) as starting materials, the title compound (60.5 mg) was obtained in the same manner as that of Reference Example 64, (1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=O)[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=[S:42])[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 58.9 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.164 g, 0.362 mmol) in toluene (3 mL) and DME (3 mL) was added Lawesson's reagent (0.117 g, 0.290 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 47%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 6.82 (d, J=10.0 Hz, 1H), 6.72 (brs, 1H), 6.47 (d, J=6.8 Hz, 1H), 4.89 (d, J=13.2 Hz, 2H), 4.16 (m, 4H), 3.85 (m, 2H), 1.64 (d, J=7.2 Hz, 3H), 1.56 (s, 3H), 1.43 (s, 9H), 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-fluorostyryl benzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ4.54 (2H, s), 6.68 (1H, d, JH,H=11.94), 7.12-7.58 (9H aromatic+1H ethylenic).