Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.[O:38]1CCCC1>>[CH3:1][C:2]1([CH3:37])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]([NH2:30])=[O:38])=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(C#N)c4)cc3)ccc2O1
Reactant: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(C(N)=O)c4)cc3)ccc2O1
Temperature: 70 °C

Procedure:
A solution of 3-({2-[4-(2-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)benzonitrile (4.6 g) in tetrahydrofuran (70 ml) was treated with potassium trimethylsilanoate (9.32 g) and heated at 70° C. for 71 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, eluted with a gradient between dichloromethane and 10% methanol in dichloromethane) to give the title compound (1.01 g). LCMS RT=2.42 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH:6]=[O:7])#N.[OH-:12].[K+].[BH4-].[Na+].Cl>CCOCC.O>[CH3:11][C:5]1([CH2:8][CH2:9][CH3:10])[CH2:6][O:7][C:1](=[O:12])[CH2:3][CH2:4]1
Reactant: CCCC(C)(C=O)CCC#N
Reactant: [OH-]
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCC1(C)CCC(=O)OC1
Temperature: 20 °C

Procedure:
A mixture of 50 g. (0.326 mole) of 2-(beta-cyanoethyl) 2-methylpentanal, 27.3 g. (0.489 mole) potassium hydroxide and 150 ml. water was stirred for four and a half hours at reflux temperature. The reaction mixture was cooled to 20° C. and a solution of 13.6 g. (0.359 mole) sodium borohydride in 75 ml. water was added. The reaction temperature rose to 50° C. Stirring was continued for one and a half hours during which period the temperature dropped to 20° C. again. The reaction mixture was acidified with dilute hydrochloric acid. The oil was taken up in ether, washed with water and dried. Distillation yield 39.5 g. (78%) γ-methyl-γ-propyl-δ-valerolactone boiling at 85°-86° C. at 0.6 mm; nD20 1.4599. This oil exhibits a greenish, cumarinic, coconut-like hairy odor.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[N:7]=[C:6]3[C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: c1coc(-c2nc3ccccc3[nH]2)c1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(-c4ccco4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 94.4 %

Procedure:
Using commercially available 2-(furan-2-yl)-1H-benzo[d]imidazole (62 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (146 mg, 94%) was obtained.
Reaction SMILES: CO[CH:3]1[C:12]2C(=CC=C[CH:11]=2)C(C)[CH2:5][CH2:4]1.[CH:14]([C:17]1[CH:31]=[C:30]([CH3:32])[C:29](C=CC=CC)=[CH:28][C:18]=1[O:19][C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:31]=[C:30]([CH3:32])[C:29]([C:12]([CH3:11])=[CH:3][CH:4]=[CH2:5])=[CH:28][C:18]=1[O:19][C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1)([CH3:16])[CH3:15]
Reactant: COC1CCC(C)c2ccccc21
Reactant: CC=CC=Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1C
Product: C=CC=C(C)c1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1C

Procedure:
Similarly prepared, following the procedure of Example 2 but starting with 4-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene instead of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-naphthalene, was 5-(2-isopropyl-4-methyl-5-penta-1,3-dienyl-phenoxy)-pyrimidine-2,4-diamine, MP=148° C., MS (M+H)=309.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH:28]([S+:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])([CH3:30])[CH3:29].C([O-])(C)(C)C.[K+].O>C(Cl)Cl>[NH2:6][C:5]1[C:12]([Cl:14])=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([N:32]=[S:31]([CH:33]([CH3:35])[CH3:34])[CH:28]([CH3:30])[CH3:29])=[O:10]
Reactant: O=c1[nH]c2c(Cl)cc(Cl)cc2c(=O)o1
Reactant: CC(C)[S+](N)C(C)C
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 276.5 %

Procedure:
To a suspension of 6,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione (45.0 g, 70.7 mmol) in methylene chloride (500 mL) was added S,S-Diisopropyl-S-aminosulfonium 2,4,6-trimethyl-phenylsulfonate (77.6 g, 234 mmol). The reaction mixture was cooled to 0° C. and potassium tert-butanolate (8.73 g, 77.8 mmol) was added after which the reaction was allowed to come to room temperature and stirred for 16 h. Water (200 mL) and methylene chloride (50 mL) were then added, the organic phase was separated and the aqueous phase further extracted with methylene chloride (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound (62.8 g, quant.).
Reaction SMILES: CC1CNC(C2C=CN=C(NC(=O)C3C=CC=CC=3)C=2)=N1.[CH2:22]([CH:26]1[CH2:30][NH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:32]=2)=[N:27]1)[CH:23]([CH3:25])[CH3:24]>>[CH2:22]([C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:45])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:32]=2)[NH:29][CH:30]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Agent: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Product: CC(C)Cc1c[nH]c(-c2ccnc(NC(=O)c3ccccc3)c2)n1
Yield: 36 %

Procedure:
Following the procedure as described in Example 10, making non-critical variations as required to replace N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide with N-(4-(4-isobutyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide, N-(4-(4-isobutyl-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained as a colorless solid in 36% yield: mp 103-105° C.; 1H NMR (300 MHz, CDCl3) δ 9.07 (br s, 1H), 8.68 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.86 (d, J=7.3 Hz, 2H), 7.73 (d, J=5.3 Hz, 1H), 7.59-7.40 (m, 3H), 6.89 (s, 1H), 2.45 (d, J=7.1 Hz, 2H), 1.98-1.79 (m, 1H), 0.90 (d, J=6.6 Hz, 6H); MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
tert-Butyl 4-(azetidin-1-ylcarbonyl)piperidine-1-carboxylate (0.50 g, 1.86 mmol) was dissolved in methylene chloride (10 mL) and to the solution was added trifluoroacetic acid (2.12 g, 18.6 mmol). The mixture was stirred at RT overnight and then the solvent was removed by evaporation. The residue was dissolved in a small amount of methanol and THF and the solution was then loaded on a cation exchange sorbent (Isolute® SCX-2; 10 g). The column washed with THF and the product was then eluted with ammonia saturated methanol. The solvent was removed by evaporation. There was obtained 0.32 g (100%) of 4-(azetidin-1-ylcarbonyl)piperidine. 1H NMR (500 MHz, CDCl3): 1.4-1.5 (m, 4H), 2.0-2.2 (m, 3H), 2.4-2.5 (m, 2H), 2.9-3.0 (d, 2H), 3.7-3.8 (t, 2H), 3.9 (s, 1H), 4.0 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:31])[C:7](=[O:30])[C:8]3[CH:18]=[C:17]([CH2:19]NC4C=CC=C([N+]([O-])=O)C=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH-].[Na+].[C:34]([OH:37])(=O)[CH3:35]>Cl>[NH2:6][C:5]1[CH:11]=[C:34]([O:37][CH2:19][C:17]2[CH:16]=[N:15][C:9]3[N:10]([CH2:13][CH3:14])[C:11]4[N:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[N:6]([CH3:31])[C:7](=[O:30])[C:8]=3[CH:18]=2)[CH:35]=[CH:3][CH:4]=1
Reactant: CC(=O)O
Reactant: CCN1c2ncc(CNc3cccc([N+](=O)[O-])c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN1c2ncc(COc3cccc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 17 h

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(3-nitrophenylamino)methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.080 g, 0.18 mmol) was dissolved in acetic acid (5 mL) and treated with a solution of stannous chloride dihydrate (0.154 g, 0.68 mmol) in concentrated hydrochloric acid (2 mL). After stirring for 17 hours the resulting mixture was made alkaline with 50% aqueous sodium hydroxide and extracted with dichloromethane (8×20 mL). The combined organics were dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) to the title compound (0.046 g, 62%), m.p. 148°-149° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH:16]2[CH2:18][CH2:17]2)=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH:16]3[CH2:18][CH2:17]3)=[CH:4][N:3]=[C:2]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)=[CH:33][CH:32]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2nc(Cl)ncc2C2CC2)cc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C4CC4)c(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 51 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-cyclopropylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 51% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.90 (dd, 1H, J=7.0, 2.0 Hz), 7.72 (m, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.22 (d, 1H, J=8.6 Hz), 7.09 (d, 2H, J=8.6 Hz), 3.45 (s, 2H), 2.43 (bs, 8H), 2.26 (s, 3H), 1.86 (m, 1H), 0.92 (m, 2H), 0.63 (m, 2H); MS (ESI): 452.3 [M+H]+, 226.9 [M+2H]2+.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([CH2:21][CH3:22])=[CH:19]C(C(=O)C)=[N:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:20]([CH2:21][CH3:22])=[CH:19][C:1]([C:2]([CH3:4])=[CH2:3])=[N:17]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CCc1cc(C(C)=O)nn1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(CC)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (3.47 g, 9.72 mmol) in THF (20 mL) was added 1 M KOt-Bu in THF (9.73 mL, 9.73 mmol) followed by the above ketone (2.10 g, 8.10 mmol). The mixture was stirred at room temperature for 4 hrs, quenched with water and extracted with ethyl acetate. The extract was dried over Na2SO4 and concentrated. The residue was slurried with hexane and filtered. The filtrate was concentrated to give the title compound as a white solid (1.46 g, 70%). mp: 61-63° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH3:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[C:26](O)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:63][C@:64]1([C:69]([NH:71][S:72]([CH:75]2[CH2:77][CH2:76]2)(=[O:74])=[O:73])=[O:70])[CH2:66][C@H:65]1[CH:67]=[CH2:68]>ClCCl>[CH:75]1([S:72]([NH:71][C:69]([C@@:64]2([NH:63][C:26]([C@@H:9]3[CH2:10][C@@H:11]([O:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]([O:24][CH3:25])=[CH:16][N:15]=4)[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:27])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:70])(=[O:74])=[O:73])[CH2:77][CH2:76]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: COc1cnc(O[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (1.1 g, 2.8 mmole) in dichloromethane (15 mL) was added HATU (1.07 g, 2.8 mmole) followed by DIPEA (2.4 mL, 14.1 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (prepared according to the procedure described in WO 03/099274) was added to the reaction mass and stirred at room temperature for 30 min. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (70% ethyl acetate in pet ether) to get 1.3 g (76.4%) of (2S,4R)-tert-butyl 2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate as a white solid. MS: MS m/z 601.2 (M++1).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:15])(=O)/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[ClH:16]>>[C:5]([Cl:16])(=[O:15])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC/C=C/C(=O)O
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: CCCCCC/C=C/C(=O)Cl
Temperature: 130 °C
Yield: 91 %

Procedure:
Thionyl chloride (131 g, 1.1 mole) is added to trans-2-nonenoic acid (156 g, 1.0 mole). Reaction occurs immediately with the evolution of HCl and SO2. After the initial reaction subsides, the mixture is heated slowly to 130°C. The dark mixture is vacuum distilled to yield trans-2-nonenoyl chloride, b.p. 90°C/2 mm, 155 g, 91% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CC([O:29]O)(C)C.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:29])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 30 h
Yield: 37 %

Procedure:
At room temperature, 1.307 g of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole, 0.059 g of tetrabutyl ammonium bromide as an interphase transfer catalyst, and 0.157 g of Mo(acac)2 oxidation catalyst were mixed in 15 ml of IPA. Next, 1.36 g of TBHP (70% aqueous solution) was added into the mixture in about 5–10 minutes. The reaction was carried out for about 30 hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 37% (HPLC purity>96%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([N+:24]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)[C:12]([NH2:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(benzyloxy)-N-(4-ethylphenyl)-3-nitropyridin-2-amine (987 mg, 2.82 mmol in AcOH (6.0 mL) was added zinc dust (737 mg, 11.2 mmol). The mixture was stirred overnight at room temperature, filtered through Celite®, and concentrated. The crude residue was dissolved in EtOAc and washed with saturated NaHCO3. The organics were dried over MgSO4, filtered, and concentrated to give the title compound as a dark brown oil (716 mg). 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.6 Hz, 2H), 2.95 (broad s, 2H), 5.32 (s, 2H), 6.20 (d, J=8.1 Hz, 1H), 6.65 (broad s, 1H), 7.05 (d, J=8.1 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.28-7.41 (m, 8H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2cccc(NS(C)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-acetylamino-2-(3-aminobenzoyl)-6-chloroindole (Example 135) and methanesulfonyl chloride. m.p.: 133-142° C. (ethyl acetate/hexane)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:19])[C:13]4[CH:14]=[N:15][NH:16][C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:20]1(=O)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[O:21]1.CN(C=O)C>ClCCl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([N:19]4[C:20](=[O:21])[C:24]5[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22]4=[O:29])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
A mixture of 6-(1H-indol-4-yl)-1H-indazol-4-amine (500 mg, 2.014 mmol), 2-benzofuran-1,3-dione (298 mg, 2.014 mmol) and DMF (2.5 ml) was placed in a Biotage vial (2-5 ml) equipped with a magnetic stirrer bar. The vial was placed in a Biotage Initiator microwave and heated at 150° C. for 30 min then again at 150° C. for a further 15 min. The reaction mixture was evaporated to dryness to give a brown oil which was dissolved in dichloromethane and applied to a 100 g silica SPE cartridge. The cartridge was eluted on a Flashmaster (II) instrument using a gradient of 0-100% ethyl acetate in cyclohexane over 40 min followed by 0-20% methanol in cyclohexane over 15 min. Appropriate fractions were combined and evaporated to give the title compound (481 mg) as a pale yellow foam.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[Cl:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[Cl:28]
Reactant: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (503 mg, 1.03 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO3 (aq.). The aqueous layer was washed with CH2Cl2 (30 mL). The combined organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product as a white solid (420 mg, 75.9% yield for the two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.56 (d, m, 1H), 7.33 (m, 1H), 6.50 (m, 1H), 4.75 (m, 1H), 3.83 (m, 2H), 3.58 (m, 2H). MS: m/z 461.9, [M+H].
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([S:30][CH3:31])=[N:27][CH:26]=1)[CH:20]([NH:32]C(OC(C)(C)C)=O)[C:19]2=[O:40])=[O:16])([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.CS(O)(=O)=O>C(#N)C>[NH2:32][CH:20]1[C:19](=[O:40])[N:18]2[CH:21]1[S:22][CH2:23][C:24]([C:25]1[S:29][C:28]([S:30][CH3:31])=[N:27][CH:26]=1)=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Yield: 99.2 %

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methylthio-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4 g) dissolved in acetonitrile (40 cc) is treated, at 25° C., with methanesulphonic acid (4 cc), in accordance with the working method of Example 15. Crude 7-amino-2-benzhydryloxycarbonyl-3-(2-methylthio-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) is obtained in the form of an orange oil.