Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH:13][C:21](=[O:22])[O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2cccc(N)c2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1noc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 3-[3-methyl(1,2,4-oxadiazol-5-yl)]phenyl amine (1.00 g, 5.7 mmol, prepared in sequence by the procedures described by Lin et al., J. Org. Chem., 1979, 44, 4160 and Bellamy and Ou, Tetrahedron Letters, 1984, 25, 839) in acetonitrile (25 mL) and pyridine (0.46 mL, 0.45 g, 5.7 mmol) under argon at 0° C. was treated with p-nitrophenyl chloroformate ( 1.15 g, 5.7 mmol) and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 10% citric acid, resulting in separation of a solid insoluble in either phase. The solid was collected, triturated with hexane and dried in vacuo to yield 1.59 g (82%) of the title compound, m.p. 217°-220° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:.2), Rf =0.75; M.S. (M+H)+ at 341, M.W. 340. This material contained minor impurities and was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][O:52][CH3:53])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][O:52][CH3:53])[CH2:48][CH2:49]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COCCN1CCN(c2cc(OC)c(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (200 mg, 0.43 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 241, step B) (108 mg, 0.39 mmol) and p-toluenesulfonicacid (197 mg, 0.95 mmol) were weighed into a 20 mL vial. 2 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 24 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (125 mg, 0.18 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.40 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=5.13 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.82 (d, J=8.07 Hz, 1H), 7.73 (d, J=9.16 Hz, 1H), 7.60 (t, J=7.70 Hz, 1H), 7.45-7.50 (m, 2H), 7.40 (tt, J=8.43, 6.23 Hz, 1H), 7.14-7.24 (m, 2H), 6.98 (t, J=6.97 Hz, 1H), 6.78 (s, 1H), 6.49 (d, J=5.13 Hz, 1H), 3.79 (s, 3H), 3.46 (t, J=5.87 Hz, 2H), 3.24 (s, 3H), 2.86 (t, J=4.58 Hz, 4H), 2.50-2.62 (m, 6H), 2.14 (s, 3H); MS (ESI): 705 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)(=[O:33])=[O:32])[N:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CN)n1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2ccccn2)n1
Yield: 85.7 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 12-(d) except for using tert-butyl[(6-aminomethylpyridin-2-yl)tert-butoxycarbonylamino]acetate (1.20 g, 3.56 mmol) obtained in Reference Example 12-(c), and using 2-pyridylsulfonyl chloride (640 mg, 3.60 mmol) in place of 3-pyridylsulfonyl chloride to afford the title compound (1.46 g) as a white solid. (Yield: 86%)
Reaction SMILES: Br[C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH2:27]([O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([O:34][C:35]1[C:40]([C:2]2[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:5]=[C:6]([C:8]([CH3:10])([CH3:11])[CH3:9])[CH:7]=2)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)c1cc(Br)c(C#N)c(C#Cc2ccc(NS(C)(=O)=O)cc2)c1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c(-c2cccnc2OCc2ccccc2)c1
Yield: 64.1 %

Procedure:
step 3—A sealed tube containing 94 (0.290 g, 0.67 mmol), 2-benzyloxy-3-pyridine boronic acid (0.184 g, 0.80 mmol, 141), Pd(PPh3)4 (0.220 g, 0.07 mmol) and Na2CO3 (0.609 g, 2.01 mmol) in MeOH (9 mL) and DCM (3 mL) was irradiated in a microwave reactor at 125° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between DCM and water then the aqueous layer was further extracted with DCM. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 0.230 g (64%) of N-{4-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-2-cyano-phenylethynyl]phenyl}-methanesulfonamide (96) as a light brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[NH:9][C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[NH:9][C:8]3[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1ccc2[nH]c(COc3ccc([N+](=O)[O-])cc3)nc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]c(COc3ccc([N+](=O)[O-])cc3)nc2c1
Temperature: 10 °C
Yield: 92.2 %

Procedure:
A mixture of 2-(4-nitro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (90 mg, 0.27 mmol), acetic acid (15 mL) and coned HCl (20 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10° C., neutralize with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-(4-nitro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid as a colorless powder (0.078 g, 90% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:3]=12.[CH2:17]([Mg]Cl)[CH2:18][CH3:19]>>[C:11]1([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH2:17][CH2:18][CH3:19])=[C:3]3[CH:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC[Mg]Cl
Reactant: Clc1ccnc2c1ccn2-c1ccccc1
Product: CCCc1ccnc2c1ccn2-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 1 (4.69 g, 20.5 mmol) and propylmagnesium chloride analogously as described in example 42, step 1. Yield: 3.57 g.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)=[O:31]>ClCCl.O>[OH:38][C:34]1[CH:33]=[C:32]([C:30](=[O:31])[CH2:29][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(CBr)c1cccc(O)c1
Reactant: CC(=O)Nc1ccc(CCOCCCCCCNCc2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCOCCCCCCN(CC(=O)c2cccc(O)c2)Cc2ccccc2)cc1
Yield: 52.1 %

Procedure:
A solution of N-[4-[2-[[6-[(phenylmethyl)amino]hexyl]oxy]ethyl]phenyl]acetamide (1 g), 2-bromo-1-(3-hydroxyphenyl)ethanone (0.61 g) and DEA (0.8 g) in dichloromethane (20 ml) was stirred under nitrogen for 18 h, diluted with water (20 ml), and extracted with dichloromethane (25 ml). The organic layer was washed with 8% sodium bicarbonate solution (20 ml), dried and evaporated in vacuo to give the title compound as a yellow oil (0.71 g).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:34]1[CH:33]=[C:32]([Cl:38])[CH:31]=[CH:36][C:35]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][C@@H:10]([CH3:21])[C@H:9]([OH:8])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(Cl)cc2Cl)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 1-bromo-2,4-dichlorobenzene (0.218 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g)in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 100° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was neutralised with sodium hydrogen carbonate solution (in water) and the aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a solid (0.064 g) from which the oxalate salt was prepared (0.054 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N:43]1([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH2:48][CH2:47][CH:46]([CH2:49][NH2:50])[CH2:45][CH2:44]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:50][CH2:49][CH:46]1[CH2:45][CH2:44][N:43]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH2:48][CH2:47]1)=[O:17]
Reactant: O=C(O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(c2ccncc2)CC1)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.321 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid was dissolved in 2 ml of DMF and treated with 0.148 g (1.28 mmol) of N-NEM and 0.105 g (0.321 mmol) of TOTU and 0.123 g (0.64 mmol) of C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0 to 17% MeOH in DCM.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[N:2]([C@H:3]1[CH2:8][CH2:7][C@@H:6]([OH:9])[CH2:5][CH2:4]1)[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN[C@H]1CC[C@@H](O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@@H](O)CC1

Procedure:
A well stirred solution of 100 g (774 mmol) of cis-4-Methylamino-cyclohexanol [Schut, Robert N. Analgesic 3-(methylamino)-1,2,3,4-tetrahydrocarbazole from 4-(methylamino)cyclohexanone. Fr. (1968), 3 pp. FR 1515629 19680301] in 775 ml EtOAc was treated with 1.55 l of aqueous 1M NaHCO3 and with 110 ml (774 mmol) of benzyl chloroformate (30 min, Tmax 30° C.). The phases were separated after 2 h at RT. The aqueous phase was extracted (EtOAc), the organic phases were dried (Na2SO4), filtered and evaporated. Purification by column chromatography on silica gel (hexane/EtOAc 2:1) gave 139 g (68%) of cis-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid benzyl ester, MS: 263 (M).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=O)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:54][O:55][NH3+:56]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:56][O:55][CH3:54])[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH2:39][CH3:40])[CH2:41][CH3:42])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[NH3+]
Reactant: CCC(CC)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CCC(CC)CC1CC(C#CC(=NOC)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-[3-(2-ethylbutyl)cyclobutyl]-4-oxo-5-hexynoate (9.70 g) and methanol (70 mL) were mixed. To the mixture were added sodium sulfate (4.57 g), pyridine (7.0 mL) and O-methylhydroxylammonium chloride (2.69 g). The mixture was stirred at RT overnight and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/30→1/20) to give the title compound (7.85 g).
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([N+:14]([O-])=O)[CH:9]=[C:10]([F:13])[C:11]=1[Cl:12]>O.[Fe]>[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([CH:9]=[C:10]([F:13])[C:11]=1[Cl:12])[NH2:14]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Br)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Cl)c(Br)c1Cl
Yield: 72.2 %

Procedure:
To a suspension of iron powder (135.4 g) in water (140 ml), with vigorous stirring at 50°-60° C., was slowly added concentrated hydrochloric acid (18 ml). After ethanol (350 ml) was mixed, 3-bromo-2,4-dichloro-5-fluoronitrobenzene (218.8 g) was added portionwise to the suspension at 52°-76° C. during an hour. After stirring for 75 minutes at the same temperature, the hot reaction mixture was filtered after adding benzene (500 ml) and the insoluble material was successively washed with hot ethanol (100 ml) and benzene (200 ml). The filtrate and washings were combined. The organic layers were washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was recrystallized from ethanol-water to give the title compound (141.6 g) as light brown needles, mp 126°-129.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N:20]([CH:23]([CH2:29][CH2:30]Br)[C:24](OCC)=[O:25])=[N+:21]=[N-:22].[I-].[Na+]>C(#N)C>[N:20]([CH:23]1[CH2:29][CH2:30][N:8]([C@H:7]([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[C:24]1=[O:25])=[N+:21]=[N-:22]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)OC(C)(C)C)N1CCC(N=[N+]=[N-])C1=O
Temperature: 60 °C
Yield: 18.9 %

Procedure:
To a solution of D-alanine tert-butylester (1.28 g) and N,N-diisopropylethylamine (1.22 ml) in acetonitrile (15 ml), was added a solution of ethyl 2-azido-4-bromobutanoate (1 g) and sodium iodide (0.02 g) in acetonitrile (5 ml). The mixture was heated at 60° C. for 60 h and then concentrated under reduced pressure to give a brown oil. This oil was partitioned between DCM and water. The separated organic layer was washed further with water and dried (over magnesium sulphate), and concentrated under reduced pressure. The residual brown oil was purified using Biotage™ chromatography (silica, eluting with cyclohexane:ethyl acetate 3:1) to give the title compound (0.204 g) as a mixture of two diastereoisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH:16](CCCOC)[C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][NH:22][C:21]=4[CH:26]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][NH2:50]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:21]=4[CH:26]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]([NH:50][CH3:49])=[O:45])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COCCCC(O[C@H]1CN(S(=O)(=O)c2ccc(C)cc2)[C@H](CC(C)(C)C(=O)O)C[C@@H]1c1ccc(OC)cc1)c1ccc2c(c1)NCCO2
Product: CNC(=O)C(C)(C)C[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 150 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid from (from example 65b) and methylamine are used to afford the title compound as a brown oil. Rf=0.18 (EtOAc-heptane 5:1); Rt=4.97.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:12][C:3]=12.[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH2:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>COCCOC.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]>[C:8]([C:7]1[C:2]([NH:25][C:24]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([Cl:30])=[CH:29][C:23]=2[Cl:22])=[C:3]2[S:12][C:11](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][C:4]2=[N:5][CH:6]=1)#[N:9]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)/C=C/c1cc2ncc(C#N)c(Cl)c2s1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)OC(C)(C)C)sc23)c(Cl)cc1Cl
Temperature: 90 °C
Yield: 54.7 %

Procedure:
A mixture of tert-butyl (2E)-3-(7-chloro-6-cyanothieno[3,2-b]pyridin-2-yl)prop-2-enoate (1.29 g, 3.74 mmol), 2,4-dichloro-5-methoxyaniline (862 mg, 4.49 mmol), Tris(dibenzylideneacetone)-dipalladium(0) (343 mg, 0.37 mmol), potassium phosphate (1.29 g, 5.61 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (456 mg, 1.16 mmol) in 36 mL of ethylene glycol dimethyl ether is heated at 90° C. for 3 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer is extracted with additional ethyl acetate and the organic layers are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of hexane to 40% ethyl acetate in hexane to provide 974 mg of tert-butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}prop-2-enoate as a light tan solid, mp 224° C. dec; 1H NMR (DMSO-d6) δ 1.48 (s, 9H), 3.85 (s, 3H), 6.26 (d, J=16 Hz, 1H), 7.37 (s, 1H), 7.75 (d, J=16 Hz, 1H), 7.78 (s, 1H), 7.91 (s, 1H), 8.62 (s, 1H), 9.80 (s, 1H); MS 476.0, 478.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([F:18])=[CH:11][C:5]=1[O:6][CH2:7][C:8](O)=[O:9])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[F:18][C:12]1[C:13]([NH2:15])=[CH:14][C:4]2[NH:1][C:8](=[O:9])[CH2:7][O:6][C:5]=2[CH:11]=1
Reactant: O=C(O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 92.8 %

Procedure:
A suspension of 2,4-dinitro-5-fluorophenoxyacetic acid (2.0 g) and 10% palladium-carbon (hydrated) (1.0 g) in ethanol (30 ml) was subjected to catalytic reduction at room temperature under an ordinary pressure until 1000 ml of hydrogen was absorbed. The reaction mixture was filtered, and the filtrate was concentrated to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3(4H)-one (1.3 g; yield, 92.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][CH3:14].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CNC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Into a 20 mL scintillation vial were added 3-Bromobenzenesulfonyl chloride (0.301 g, 1.179 mmol) and anhydrous pyridine (5 mL). A 2M solution of dimethylamine in THF (1.0 mL, 2.0 mmol) was added dropwise, and the reaction mixture was stirred at rt under N2 for 5 h after which it was concentrated under vacuum. The crude residue was partitioned between EtOAc and IM citric acid. The layers were separated, and the organic phase was washed 3× with 1M citric acid, then treated with brine, dried (Na2SO4), filtered and concentrated. Trituration with Et2O provided 3-Bromo-N,N-dimethyl-benzenesulfonamide as a white powder (0.297 g, 96%). MS: m/z 263.9/265.9 [MH+].