Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Br:15]Br>C(OC(=O)C)C>[Br:15][CH:10]([CH:11]([CH3:12])[CH3:13])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: BrBr
Reactant: COc1ccc(C(=O)CC(C)C)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)C(Br)C(C)C)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
While 56.9 g of 1-(4-methoxy-phenyl)-3-methyl-butan-1-one (3) prepared in Example 1 were added to 200 ml of ethylacetate and stirred, 18.2 ml of bromine were added at room temperature and stirring was continued at the same temperature for 1 hr. After the reaction was completed, the resultant reaction mixture was washed with brine and water, in that order, after which the ethylacetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, thus obtaining 77.0 g (yield: 96.0%) of a title compound as light yellow liquid.
Reaction SMILES: [C:1]1([C:11]#[N:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>C(O)(=O)C.[Pd]>[NH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#Cc1nccc2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: NCc1nccc2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 0.4999 g (3.24 mmol) 1-isoquinolinecarbonitrile (1) (Aldrich) in 15 mL glacial acetic acid was added 0.0564 g Pd (10% on C). After 16 h under H2 at atmospheric pressure, the reaction mixture was filtered over celite. The celite was washed with 75 mL EtOAc, and the filtrate was concentrated in vacuo. To this was added 100 mL n-heptane, and the mixture concentrated in vacuo. The above step was repeated three times to remove acetic acid. Purification by flash chromatography (40×220 mm silica gel, linear gradient 5-10% (10% NH4OH:MeOH):CH2C12) yielded 2. 1H NMR (CDCl3, 400 MHz) δ 8.479 (d, 1H, J=5.76 Hz, ArH); 8.135 (d, 1H, J=8.42 Hz, ArH); 7.848 (d, 1H, J=8.41 Hz, ArH); 7.714-7.673 (m, 1H, ArH); 7.639-7.597 (m, 1H, ArH); 7.563 (d, 1H, J=5.67 Hz, ArH); 4.517 (s, 2H, ArCH2); MS (FAB): m/z 159.08 (M30 H).
Reaction SMILES: C1(SSC2C=CC=CC=2)C=CC=CC=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]=2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)=[CH:18][CH:17]=1
Reactant: Cc1cccc2c1CCN=C2c1ccc(F)cc1
Agent: c1ccc(SSc2ccccc2)cc1
Product: Cc1cccc2c(-c3ccc(F)cc3)nccc12

Procedure:
Diphenyl disulfide was reacted with 1-(4-fluorophenyl)-5-methyl-3,4-dihydroisoquinoline in the same way as in step (c) of Example 1 to afford 1-(4-fluorophenyl)-5-methylisoquinoline as colorless needles having a melting point of 91° to 92° C.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:8]([CH3:34])([CH3:33])[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].[C:35]([O:59][CH:60]1[CH2:65][C:64]([CH3:67])([CH3:66])[N:63]([OH:68])[C:62]([CH3:70])([CH3:69])[CH2:61]1)(=[O:58])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH:47]1[CH2:52][C:51]([CH3:54])([CH3:53])[N:50]([OH:55])[C:49]([CH3:57])([CH3:56])[CH2:48]1)=[O:45]>>[C:35]([O:59][CH:60]1[CH2:61][C:62]([CH3:70])([CH3:69])[N:63]([O:68][CH2:3][CH2:2][C:1]([O:5][CH:6]2[CH2:7][C:8]([CH3:33])([CH3:34])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([CH3:12])([CH3:13])[CH2:11]2)=[O:4])[C:64]([CH3:67])([CH3:66])[CH2:65]1)(=[O:58])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH:47]1[CH2:48][C:49]([CH3:56])([CH3:57])[N:50]([O:55][CH2:3][CH2:2][C:1]([O:5][CH:6]2[CH2:7][C:8]([CH3:33])([CH3:34])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([CH3:12])([CH3:13])[CH2:11]2)=[O:4])[C:51]([CH3:53])([CH3:54])[CH2:52]1)=[O:45]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: C=CC(=O)OC1CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C1
Product: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC3CC(C)(C)N(OCCC(=O)OC4CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C4)C(C)(C)C3)CC2(C)C)CC1(C)C

Procedure:
The title compound is prepared from 1-octadecyloxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate and bis(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate according to the general procedure of Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:12])=[O:13])=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To 1-(3-nitro-4-chloro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine (3.6 g, 10 mmol) in THF (50 mL) and water (50 mL) was added sodium hydrosulfite (10.2 g, 50 mmol). The mixture was stirred at ambient temperature for 2 hrs. Ethyl acetate (150 mL) and sat. NH4Cl (150 mL) were added. The organic layer was separated, washed with brine (2×50 mL) and dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (4/1 to 1/1) yielded 2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenylamine as pale yellow solid (3.4 g). MS: 337.0 (M+H)+; tR=2.85 min (method 1).
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]1([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15]1)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([C:14]1([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[CH2:15][CH2:16][CH2:17]1)[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CCOC(=O)COc1ccc(C2(C(CC(C)C)NC(=O)OC(C)(C)C)CCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C2(C(N)CC(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 69 (0.25 g, 0.0005 mole) in 20 mL of 1:1 mixture of DCM and trifluoroacetic acid (TFA) was stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), washed with brine (25 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by 0-100% gradient of ethyl acetate and hexane as eluent to give the pure amine 70 as colorless oil in 85% (0.13 g) yield. 1H NMR (400 MHz, CDCl3): δ 0.85 (3H, broad s); 0.83 (3H, broad s); 1.25 (3H, t, J=4.5 Hz); 1.59 (1H, m); 1.85 (2H, m); 1.93 (2H, m); 2.20 (2H, m); 2.42 (2H, m); 2.68 (2H, m); 3.21 (1H, m); 4.08 (2H, q, J=4.5 Hz); 5.09 (2H, s); (6.81 (2H, broad d); 7.13 (2H, broad d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:22][CH:23]([F:35])[CH2:24][O:25][C:26]1[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH2:24][CH:23]([F:35])[F:22])=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: O=C(O)c1cnc(OCC(F)F)cn1
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3cnc(OCC(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-2) and 5-(2,2-difluoroethoxyl)pyrazine-2-carboxylic acid [Y. Suzuki et al. WO2009091016 (2009)] following General Procedure G yielded the title compound as a colorless solid. MS: m/z=496.6 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:31](=[O:32])[N:30]([CH3:33])[C:12]3[N:13]([CH3:29])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][C:17]([C:20]2[NH:21][N:22]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:24]=2)=[CH:16][CH:15]=4)=[CH:5][CH:4]=1.Br[C:35]1C=CC(C2C(=O)N(C)C3N(C)C4C(C=3C=2)=CC(C2C=C(COCC)NN=2)=CC=4)=CC=1.IC>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:31](=[O:32])[N:30]([CH3:33])[C:12]3[N:13]([CH3:29])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[N:22]([CH3:35])[N:21]=2)=[CH:16][CH:15]=4)=[CH:5][CH:4]=1
Reactant: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)n[nH]1
Reactant: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)[nH]n1
Agent: Cl
Solvent: CI
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with the compound from Example 84, 3-(4-bromophenyl)-6-(5-ethoxymethyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane.
Reaction SMILES: [SH:1][C:2]([C@H:5]1[O:10][C:8](=[O:9])[C@@H:7]([CH2:11][SH:12])[CH2:6]1)([CH3:4])[CH3:3].Cl>C1COCC1.[OH-].[Na+]>[C:8]([C@@H:7]1[CH2:11][S:12][C@@H:5]([C:2]([SH:1])([CH3:4])[CH3:3])[CH2:6]1)([OH:10])=[O:9]
Reactant: CC(C)(S)[C@@H]1C[C@H](CS)C(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(S)[C@H]1C[C@H](C(=O)O)CS1
Reaction time: 0.5 h

Procedure:
To a stirred solution of cis-4-(1-mercapto-1-methylethyl)-2-mercaptomethyl-4-butanolide (1.1 g) in THF (4 ml), 1N sodium hydroxide solution (5.2 ml) was added and the mixture was stirred for 30 minutes. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give the titled compound (compound No. 8-1) quantitatively.
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[C:27](\[Br:34])/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([OH:37])=[O:36].[C:39]([C@@H:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43]=1)#[N:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:23]1([CH3:22])[C@@H:25](/[CH:26]=[C:27](\[Br:34])/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([O:37][C@H:41]([C:39]#[N:40])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:43]=1)=[O:36]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
0.9 ml of pyridine and 2.1 g of dicyclohexylcarbodiimide were added to a solution of 2.9 g of the product of Step B in 40 ml of methylene chloride and the mixture was stirred for 15 minutes. A solution of 2.5 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 15 ml of methylene chloride and then 25 mg of 4-dimethylamino-pyridine were added to the reaction mixture which was stirred for 2 hours and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 4.26 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-2-propoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate melting at 64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[CH:15]([Si:18]([CH3:40])([CH3:39])[C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>>[CH:15]([Si:18]([CH3:40])([CH3:39])[C:19]1[CH:38]=[CH:37][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:16])[CH3:17]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)[Si](C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Product: CC(C)[Si](C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [4-(isopropyl-dimethyl-silanyl)-benzyl]-[2-(3-trifluoromethyl-phenyl)-ethyl]-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [4-(isopropyl-dimethyl-silanyl)-benzyl]-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine. MS (ISP) 575.3/576.4/577.3 (100/46/40) (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[C:19]#[CH:20])[CH3:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[F:1][C:2]1[C:3]([C:20]#[C:19][C:18]([O:21][CH2:22][CH3:23])([O:17][CH2:15][CH3:16])[O:24][CH2:25][CH3:26])=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(F)c1I
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)Cc1cccc(F)c1C#CC(OCC)(OCC)OCC
Temperature: 60 °C
Yield: 35.9 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (456 mg, 0.649 mmol), cuprous iodide (371 mg, 1.95 mmol), and ethyl 2-(3-fluoro-2-iodophenyl)acetate (2.0 g, 6.49 mmol), were mixed in a 20 mL microwave tube. The tube was sealed, and ACN (12 mL) and TEA (6 mL) were added. The mixture was placed under argon atmosphere and 3,3,3-triethoxyprop-1-yne (1.68 g, 9.74 mmol) was added via syringe. The reaction was heated at 60° C. for 16 hours, cooled to room temperature, and concentrated under vacuum. The residue was purified by flash chromatography to give 820 mg of ethyl 2-(3-fluoro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)acetate as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33])[CH2:12][CH2:11][CH:10]=[C:9]3B1OC(C)(C)C(C)(C)O1.I[C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1.[OH-].[Ba+2].[OH-]>C(#N)C.O.Cl>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33])[CH2:12][CH2:11][CH:10]=[C:9]3[C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1csc(I)n1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(C)cs2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,3-dimethyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-m-tolyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (step 5) (295 mg, 0.66 mmol), 2-iodo-4-methylthiazole (Intermediate O) (135 mg, 0.60 mmol), Pd-118 (19.6 mg, 0.03 mmol) and barium hydroxide (206 mg, 1.20 mmol) in acetonitrile/water (1:1, 3 mL) was stirred at 80° C. for 30 minutes. The reaction mixture was diluted with 1M HCl (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were filtered through a hydrophobic frit and the solvent was removed under vacuum. The residue was purified by chromatography on silica, eluting with 1-2% MeOH/DCM to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH3:2].Br[CH2:21][C:22]#[N:23].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH2:21][C:22]#[N:23])[CH3:2]
Reactant: CCOC(=O)Cc1c(F)cnc2ccc(OC)nc12
Reactant: N#CCBr
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC#N)c1c(F)cnc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
LiRMDS in THF (1M; 12.5 mL) was added at −78° C. during 15 min to a solution of (3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-acetic acid ethyl ester (3.00 g; prepared in analogy to the corresponding methyl ester described in WO 2007/122258) in THF (30 mL). The resulting orange mixture was stirred at −78° C. for 2 h. Bromoacetonitrile (1.13 mL) was added dropwise and the reaction mixture was further stirred at −78° C. for 2 h. The reaction mixture was treated with water and extracted with EA. The combined org. phases were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by CC (Hept/EA 2:1 to 1:1) affording a yellow oil (3.09 g; 89.7% yield).
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[C:44](=[O:45])[N:43]([CH2:46][C:47]3[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=3)[N:42]=[CH:41]2)[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[C:44](=[O:45])[N:43]([CH2:46][C:47]3[O:48][C:49]([C:52]([F:54])([F:53])[F:55])=[CH:50][CH:51]=3)[N:42]=[CH:41]2)[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)o3)c2=O)sc1C(=O)O
Yield: 84 %

Procedure:
Following the procedure as described in Example 20, making variation as required to replace ethyl 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(5-oxo-1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: MS (ES−) m/z 373.0 (M−1).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1)[CH3:4].[N+:16]([C:19]1[CH:25]=[CH:24][C:23](Cl)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17]>O.CN(C)C=O>[N+:16]([C:19]1[CH:25]=[CH:24][C:23]([S:13][C:11]2[S:12][C:8]3[CH:7]=[C:6]([O:5][CH2:3][CH3:4])[CH:15]=[CH:14][C:9]=3[N:10]=2)=[CH:22][C:20]=1[NH2:21])([O-:18])=[O:17]
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2nc(Sc3ccc([N+](=O)[O-])c(N)c3)sc2c1
Reaction time: 16 h

Procedure:
To a stirred solution of 0.15 moles of potassium hydroxide in a mixture of 15 ml of water and 300 ml of dimethylformamide add 0.15 moles of 6-ethoxybenzothiazole-2-thiol (L. B. Sebrell and C. E. Boord, J. Am. Chem. Soc., 45, 2390 (1923)) under a nitrogen atmosphere. After complete dissolution, add 2-nitro-5-chloroaniline (R. C. Fuson, R. A. Dauman, E. Howard, Jr., and E. N. Marvell, J. Org. Chem., 12, 084 (1947)) and heat the mixture under reflux and a positive nitrogen pressure for about 16 hours. Pour the mixture into 1000 ml of water and remove the resulting precipitate. Wash the precipitate with water and crystallize from acetonitrile to give the title compound having a melting point of 126°-129° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:15])=[CH:11][C:12](=O)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17]O.C([O-])(=O)C.[Na+]>CO>[CH2:1]([CH:8]1[CH:13]=[C:12]([NH2:17])[CH:11]=[C:10]([CH3:15])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)cc(Cc2ccccc2)o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=CC(N)=CC(Cc2ccccc2)O1
Reaction time: 8 h

Procedure:
This amine was prepared according to Scheme 32. To 0.37 g (1.8 mmol) of 2-benzyl-6-methyl-4-pyranone (G. Piancatilli, et. al., Synthesis, 1982, 248) was added 0.22 g (3.1 mmol) of hydroxylamine hydrochloride and 0.16 g (2 mmol) of sodium acetate in 10 mL of methanol. After stirring overnight, the mixture was partitioned between CH2Cl2 and water. The organic phase was dried and evaporated. The oily residue solidified upon standing at room temperature to give 0.4 g (99%) of the desired oxime 121 as a Z/E isomer mixture 1:1 by GC/MS with a molecular ion of 219, and that was used as is in the reduction reaction below.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:42][CH2:41][C:18]2[C:19]3[C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[O:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:23][CH:22]=[N:21][C:20]=3[S:40][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:24]2[C:19]3[C:18]4[CH2:41][CH2:42][NH:15][CH2:16][C:17]=4[S:40][C:20]=3[N:21]=[CH:22][N:23]=2)=[C:27]([O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)c(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
Trifluoroacetic acid (0.50 mL) was added into a solution of 4-[4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenylamino]-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.031 g, 0.06 mmol) in DCM (1 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DCM and washed with 2M NaOH. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was washed with hexane to afford the title compound as a white solid (0.016 g, 65%).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH2:6][CH2:5][C:4]([C:14]([O:16]CC)=O)=[CH:3]1.Br[CH2:20][Cl:21].C([Li])CCC.CCCCCC.P([O-])([O-])([O-])=O>C1COCC1.C(OCC)(=O)C>[Cl:21][CH2:20][C:14]([C:4]1[CH2:5][CH2:6][N:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[C@@H:2]([CH3:1])[CH:3]=1)=[O:16]
Reactant: ClCBr
Reactant: C=CCOC(=O)N1CCC(C(=O)OCC)=C[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOC(=O)N1CCC(C(=O)CCl)=C[C@@H]1C
Temperature: 0 °C
Yield: 82 %

Procedure:
To a solution of 1-allyl 4-ethyl (6S)-6-methyl-3,6-dihydro-1,4(2 H)-pyridinedicarboxylate (200 mg, 0.79 mmol) and bromochloromethane (0.082 ml, 1.3 mmol) in THF (4 ml) was added at −90° C. a solution of n-butyllithium in hexane (1.59M, 0.74 ml, 1.2 mmol). Twenty minute later, the reaction mixture was poured into a mixture of ice (5 g) and phosphate buffer (pH 7.0, 10 ml). To the solution was added ethyl acetate and after separating the mixture with a separating funnel, the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give allyl (6S)-4-(chloroacetyl)-6-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (167 mg).