Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:61]1[CH:62]=[N:63][CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:61]2[CH:62]=[N:63][CH:64]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:66]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cncc(C(F)(F)F)c2)ccn1
Yield: 46.4 %

Procedure:
A microwave vial was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.200 g, 0.806 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.159 g, 0.275 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.086 g, 0.083 mmol). Degassed dioxane (10 ml) was added, followed by 3-bromo-5-(trifluoromethyl)pyridine (0.223 g, 0.991 mmol) and cesium carbonate (0.527 g, 1.62 mmol) The vial was then irradiated in a microwave oven at 150° C. for 90 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with dichloromethane/methanol 100:0→90:10 gradient to yield the title compound (0.147 g, 46%) as an off-white solid, MS (ISP): m/e=394.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:38]1[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:45])[F:46])=[CH:40][CH:39]=1)(=[O:43])=[O:42]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-(trifluoromethoxy)benzenesulfonyl chloride (18 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethoxy)benzenesulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[OH:30][C@:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[C:3]([CH3:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:7](=[N:14][C:13]([C:15]([NH2:17])=[O:16])=[CH:12]3)[C:6]=2[CH:18]=1
Reactant: Cc1cc2c(cc1Br)-c1nc(C(N)=O)cn1CCO2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2C)OCCn2cc(C(N)=O)nc2-3)no1

Procedure:
Following Procedure F, 10-bromo-9-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid after purification by reverse-phase HPLC. LCMS: 393.1 [M+H]+; 1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 7.76 (s, 1H), 7.49 (s, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.95 (s, 1H), 6.45 (s, 1H), 6.35 (s, 1H), 4.46 (s, 4H), 2.41 (s, 3H), 2.34 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Cl.Cl[CH2:54][C:55]1[N:59]([CH3:60])[N:58]=[N:57][CH:56]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:54][C:55]3[N:59]([CH3:60])[N:58]=[N:57][CH:56]=3)[N:39]=2)[N:36]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Cn1nncc1CCl
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: Cl
Product: Cn1nncc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light yellow gum. MS (m/e): 358.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:22](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)\[C:23]#[N:24])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: N#CCc1ccccn1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3ccccn3)cc2c1
Yield: 96.8 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 2-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 311 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14](Cl)=[O:15].[NH:17]1[CH:21]=[CH:20]N=N1.C([O-])([O-])=O.[K+].[K+].O>S1(CCCC1)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14]1[O:15][CH:20]=[CH:21][N:17]=1
Reactant: c1c[nH]nn1
Reactant: O=C(Cl)Cc1cc(-c2ncco2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Brc1ccc(-c2ncco2)cc1Cc1ncco1
Temperature: 140 °C

Procedure:
A mixture of the title compound of Step (C), 1H-1,2,3-triazole (144 mg, 2.1 mmol) and K2CO3 (1.3 g, 9.5 mmol) in 3.8 ml sulfolane was heated at 140° C. for 3 hrs. After cooling, 30 ml H2O was added and the mixture was extracted with 1:1 EtOAc/hexane. The combined organic extracts were washed with H2O and brine, dried and concentrated. The residue was chromatographed on silica gel using 3:1 hexane/EtOAc to afford the title compound of this step (256 mg, 44% for three steps).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4.3 Parts of sarcosine and 4.1 parts of sodium hydroxide are dissolved in 100 parts of water. To the resulting solution, 35 parts of chloroform containing 10 parts of p-chlorobenzenesulfonyl chloride is added, and the resulting mixture is stirred at 60° C. for about 2 hours. After the reaction, the aqueous layer is separated and then acidified with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and recrystallized from a mixed solvent comprising acetone and water to obtain 4.6 parts of N-p-chlorobenzenesulfonyl-sarcosine, m.p. 180.5°-182° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(#N)C.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([CH:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[CH2:20][CH2:19]1>O>[CH2:8]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]([CH:27]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[O:34][C:35]3[C:40]2=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])[CH2:22][CH2:23]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(NC1CCNCC1)C1c2ccccc2Oc2ccccc21
Reactant: CCCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCN1CCC(NC(=O)C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
60 mg of potassium carbonate and 25 ml of iodohexane were successively added to 5.0 ml of acetonitrile suspension having 50 mg of N-(piperidin-4-yl)xanthene-9-carboxamide hydrochloride, followed by reflux under heating for 4 hours. After cooled to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by preparative thin layer chromatography (Kieselgel™60F254, Art5744 produced by Merck Co.: chloroform/methanol=10/1), and 35 mg of the title compound as a white solid was obtained.
Reaction SMILES: COC1C=C(C2C3C(=NC=CC=3)NC=2)C=CC=1OC.[F:20][C:21]([F:38])([F:37])[CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[C:34]([OH:36])=O.[CH:39]1([O:44][C:45]2[CH:46]=[C:47]([C:53]3[C:61]4[C:56](=[N:57][CH:58]=[CH:59][CH:60]=4)[NH:55][CH:54]=3)[CH:48]=[CH:49][C:50]=2[O:51][CH3:52])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([O:44][C:45]2[CH:46]=[C:47]([C:53]3[C:61]4[C:56](=[N:57][CH:58]=[CH:59][CH:60]=4)[N:55]([C:34]([C:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:32]=[CH:33][C:24]=4[O:23][CH2:22][C:21]([F:20])([F:38])[F:37])=[O:36])[CH:54]=3)[CH:48]=[CH:49][C:50]=2[O:51][CH3:52])[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC1CCCC1
Reactant: O=C(O)c1c(OCC(F)(F)F)ccc2ccccc12
Agent: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Product: COc1ccc(-c2cn(C(=O)c3c(OCC(F)(F)F)ccc4ccccc34)c3ncccc23)cc1OC1CCCC1

Procedure:
[3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-[2-(2,2,2-trifluoro-ethoxy)-naphthalen-1-yl]-methanone 124 was prepared using the same protocol as described in Example 47, substituting 2-ethoxy-4-nitro-benzoic acid and 3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine with 2-(2,2,2-Trifluoro-ethoxy)-naphthalene-1-carboxylic acid and 3-(3-cyclopentoxy-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine. MS(ESI) [M+H+]+=561.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:38]([C:39]#[N:40])[C:41]#[N:42])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 77.4 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 135 mg (0.40 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 110 mg (0.43 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3.5 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with methanol to give 178 mg of a dark brown crystal (yield: 78.1%; mp: 159-161° C.)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=3[OH:24])=[C:11]([F:25])[CH:10]=2)[CH2:4]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl.O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][C:26](=[O:28])[CH3:27])[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:25])=[C:17]([OH:24])[CH:18]=1)[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(Oc2ccc(N3CC(CN)OC3=O)cc2F)c(O)c1
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(Oc2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a solution of 5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-oxazolidin-2-one (10 mg, 0.028 mmol) in 2 ml of dry dichloromethane, cooled to 0° C., was added acetic anhydride (3 mg, 0.028 mmol) taken in 0.2 ml of dichloromethane. The reaction mixture was warmed to rt and stirred for 5 minutes until reaction was complete on TLC. The reaction mixture was diluted with 3 ml of water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic fraction was dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was purified by preparative HPLC (Column: C18 Symmetry (300×19 mm), 7μ, Mobile phase A: 20 mM ammonium acetate, Mobile phase B: Acetonitrile) to get 6 mg, 55.2% of the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]1([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]>CO.[Ni]>[CH2:24]([NH:23][C:6]1([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[CH:10][CH2:11]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC1(NCCCC)C=CC(C=Cc2ccc([N+](=O)[O-])cc2)=CC1
Agent: [Ni]
Solvent: CO
Product: CCCCNC1(NCCCC)C=CC(CCc2ccc(N)cc2)=CC1
Yield: 92.5 %

Procedure:
The title compound was prepared from 1,1-dibutylamino-4-[2-(4-nitrophenyl)ethenyl]benzene (4.10 g, 11.63 mmol) and Ra—Ni (2.0 g) in MeOH (100 mL) at 21° C. to 32° C. (ΔP=3.6 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a colorless oil, 3.49 g (10.76 mmol, 92.6%) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]2[S:8][CH2:9][CH2:10][N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[CH:5]=1)([O-])=O.I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>C(O)C.O1CCCC1.C(OCC)(=O)C.[Pd]>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](=[NH:34])[NH:1][C:4]1[CH:26]=[CH:25][C:7]2[S:8][CH2:9][CH2:10][N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[CH:5]=1
Reactant: CSC(=N)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccc([N+](=O)[O-])cc32)CC1
Agent: [Pd]
Agent: I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccc(NC(=N)c4cccs4)cc32)CC1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A suspension of tert-butyl 4-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)piperidine-1-carboxylate (468 mg, 1.233 mmol) and palladium, 10 wt. % on activated carbon (131 mg, 0.123 mmol) in ethanol (10 mL) and tetrahydrofuran (1 mL) was stirred under an atmosphere of hydrogen (balloon pressure) for 2 hours. During this time, the reaction mixture turned colorless. To the mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (528 mg, 1.850 mmol), and the resulting suspension was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 1:5 ethyl acetate:dichloromethane to give the desired product (403 mg, 71.2%). 1H NMR (DMSO-d6) δ 7.72 (d, J=3.0 Hz, 1H), 7.59 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.42-6.28 (m, 3H), 6.13 (d, J=8.1 Hz, 1H), 4.06-3.95 (m, 2H), 3.85-3.76 (m, 1H), 3.40-3.33 (m, 2H), 2.99-2.93 (m, 2H), 2.92-2.75 (m, 2H), 1.69-1.48 (m, 4H), 1.39 (s, 9H); ESI-MS (m/z, %): 459 (MH+, 100).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:18])[CH3:17]>C1C=CC=CC=1>[C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: c1ccccc1
Product: CC(=O)N1c2ccccc2NC(=O)c2cscc21
Reaction time: 8 h

Procedure:
A reaction mixture comprising 9.9 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4 g. (3.7 ml.) of acetyl chloride in 100 ml. of benzene is refluxed for 3 hours and then allowed to stand at room temperature overnight. The precipitate is collected, washed with benzene and dried. The solid is crystallized twice from hot methanol with cooling giving the desired product, mp. 228°-230° C.
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[CH:12]=[O:13].[Cl-].[NH4+]>C(OCC)C>[OH:17][C:16]1[C:15]([CH3:18])=[CH:14][C:11]([CH:12]([CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[OH:13])=[CH:10][C:9]=1[CH3:8]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: C[Si](C)(C)CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(C(O)C[Si](C)(C)C)cc(C)c1O
Temperature: 0 °C

Procedure:
Mix magnesium turnings (240 mg, 10 mmol) and anhydrous ethyl ether under an inert atmosphere. Add a solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (1.5 g, 10 mmol) in anhydrous ethyl ether. Stir until reaction is complete. Cool the reaction mixture to 0° C. and add saturated ammonium chloride solution. Separate the ether layer, wash with water and dry (MgSO4). Evaporate to give 4-hydroxy-3,5-dimethyl-α-[(trimethylsilyl)-methyl]benzenemethanol and purify by silica gel chromatrography.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)N1.CC1C=C[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2N=1.CC1CCC2C(CCCC2)N1>>[CH3:17][CH2:16][CH2:15][CH2:20][CH2:19][CH2:18][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:9][CH2:10][CH2:11][CH2:2][CH3:1]
Reactant: Cc1ccc2c(n1)CCCC2
Reactant: CC1CCc2ccccc2N1
Agent: CC1CCC2CCCCC2N1
Product: CCCCCCCCCCCCCCCC

Procedure:
The autoclave was cooled and the contents were suction filtered. Gas liquid chromatographic analysis of the colorless liquid filtrate on a 6'×1/8" 10% Carbowax 20M column at 200° C. showed that the only product of the reaction was 2-methyl-1,2,3,4-tetrahydroquinoline (96% 2-methyl-1,2,3,4-tetrahydroquinoline and 4% starting material). There were no detectable amounts of 2-methyl-5,6,7,8-tetrahydroquinoline and 2-methyldecahydroquinoline. Gas liquid chromatographic analysis with an external standard showed that the absolute yield of product based on consumed starting material was 100%. The use of cyclohexane as the solvent instead of n-hexadecane gave the same result (97% of 2-methyl-1,2,3,4-tetrahydroquinoline and 3% of 2-methylquinoline).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][C:19]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22]3)=[N:18][C:17]=2[CH2:30]O)=[CH:12][CH:11]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[Na].FC(F)(F)CO>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][C:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]#[N:29])[CH2:25][CH2:26]3)=[N:18][C:17]=2[CH2:30][O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[CH:12][CH:11]=1
Reactant: OCC(F)(F)F
Reactant: N#CCN1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCN1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3)o2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 5-l round bottom flask containing sodium hydride (60% dispersion, 180 g, 4.5 mole) and tetrahydrofuran (1.5 l) is cooled to 0° C. and 2,2,2-trifluoroethanol (516 mL, 7.2 mole) is added over 1 hour. A separate 12-l round bottom flask containing {4-[5-(4-fluorophenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl} acetonitrile (300 g, 0.90 mole), tetrahydrofuran (6.0 l) and triethylamine (500 mL, 3.6 mole) is cooled to -3° C. then methanesulfonic anhydride (360 g, 2.1 mole) is added in one portion. The resulting suspension is stirred for 30 minutes then the 2,2,2-trifluoroethanol sodium salt solution in the 5-l round bottom flask is added in one portion. The resulting slurry is warmed to room temperature, stirred for 1 hour, concentrated to a semi-solid and water (4.5 l) is added. The suspension is washed with methyl t-butylether (2×3 L). The combined organic extracts are washed with water (1.5 l), saturated aqueous sodium chloride (1.5 l), dried over sodium sulfate (100 g), filtered and concentrated to 1 l. To effect crystallization, heptane (4 l) is added. The resulting slurry is cooled to 0° C., the solids are collected by filtration and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidin-1-yl} acetonitrile (318 g, 0.801 mole). H NMR (400 MHz, CDCl3) d 1.99 (m, 2H), 2.20 (m, 2H), 2.54 (t, 2H), 2.90 (m, 3H), 3.60 (s, 2H), 4.00 (q, 2H), 4.70 (s, 2H), 7.16 (t, 2H), 7.73 (q, 2H).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH2:6][C@@H:5]([NH:30][S:31]([CH:34]2[CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH2:4]1)[CH3:2].[OH-].[Na+].Cl>O1CCOCC1.CCOC(C)=O.O>[CH2:1]([C@H:3]1[C@@H:7]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH2:6][C@@H:5]([NH:30][S:31]([CH:34]2[CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1cnc2cnc3[nH]ccc3c21
Temperature: 80 °C
Yield: 45 %

Procedure:
A mixture of N-((1S,3R,4S)-3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.119 g, 0.214 mmol) and 1N aqueous NaOH (0.428 mL, 0.428 mmol) in 1,4-dioxane (2 mL) was heated at about 80° C. for about 40 min. Aqueous NaOH (1 N, 0.428 mL, 0.428 mmol) was added and the reaction mixture was heated at about 80° C. for about for 3.5 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The residue was dissolved in EtOAc (10 mL) and water (10 mL). The pH was adjusted to about 5 by the addition of 1 N aqueous HCl. The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was triturated with Et2O (5 mL) and the solvent was removed by pippette. The residue was dried under reduced pressure to give a bright yellow solid that was purified by chiral chromatography [Table 2, Method 39, Rt=16.6 min, or =negative) to give N-((1S,3R,4S)-3-ethyl-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.036 g, 45%): LC/MS (Table 1, Method a) Rt=1.71 min; MS m/z 374 (M+H)+.