Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([OH:3])=[O:2].[CH2:18](O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:18][CH3:19])=[O:2]
Reactant: O=C(O)CCCCCCCCC1=CCCC1=O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCCCC1=CCCC1=O

Procedure:
The acid ketone from Example 22 is Fisher esterified with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139° C. (0.05 Torr).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.[CH:19](O)(C)C>[Pd]>[CH3:3][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: CC(C)O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: Cc1c(C(=O)OC(C)C)[nH]c2ccccc12
Yield: 25 %

Procedure:
Sodium borohydride (0.23 g) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (0.2 g) and 10% palladium on carbon (0.11 g) in isopropanol (45 ml). The solution was heated at reflux for 4 hours, cooled and filtered through Celite. The solution was partitioned between ethyl acetate and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give the desired end product as a white solid (0.05 g, 25%); NMR δ(CD3SOCD3) 1.3 (d, 6H), 2.5 (s, 3H), 5.2 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.6 (d, 1H), 11.3 (bs, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:34][N:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:35]([CH3:34])[C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc([N+](=O)[O-])cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 539.6 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].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>CN(C=O)C.O>[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1cccc(CC(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2,3-dimethylphenyl)acetic acid (33.9 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 2.12 (s, 3H), 2.27 (s, 3H), 3.24-3.31 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.24-4.32 (m, 2H), 7.03 (d, J=6.82 Hz, 2H), 7.05-7.09 (m, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.52 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: N.Cl[C:3]1(Cl)[CH:10]2[CH:4]1[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[N:7](C=O)[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=12.[Na].[Cl-].N>>[CH2:3]1[CH:4]2[CH:10]1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=12
Reactant: O=CN1c2ccccc2C2C(c3ccccc31)C2(Cl)Cl
Agent: N
Agent: [Cl-]
Agent: [Na]
Product: c1ccc2c(c1)Nc1ccccc1C1CC21
Reaction time: 1 h
Yield: 53 %

Procedure:
In 20 ml. of liquid ammonia is suspended 1.824 g. of 1,1-dichloro-1a,10b-dihydrodibenzo(b,f)cycloprop(d)azepine-6(1H)-carboxaldehyde, and while the suspension is stirred at -40° to -50° C,0.69 g. of small pieces of sodium metal are added. The system is stirred atthe same temperature for 1 hour, after which time 1.5 g. of ammonia chloride is added. The liquid ammonia is distilled off and 20 ml. of wateris added. The mixture is extracted three times with 20 ml. portions of benzene and the extracts are washed with water and dried. The benzene extracts are passed over a column packed with silica gel and then adsorbedmaterial is eluted by means of a mixed solvent of benzenecyclohexane (6:4).The eluate is concentrated, whereby 0.658 g. (53 %) of 1,1a,6,10b-tetrahydrodibenzo(b,f)cycloprop(d)azepine is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[CH:58]([NH2:60])[CH3:59]>O1CCCC1.C(Cl)Cl.C(O)C>[NH:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[CH:58]([NH:60][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:59]
Reactant: CC(N)c1nc2ccccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(=O)NC(C)c2nc3ccccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 83 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 83%; Rf value: 0.67 (silica gel; methylene chloride/ethanol=9:1); C22H24N4O2 (376.46); mass spectrum: (M+H)+=377.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](B(O)O)=[CH:7]2.Cl[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:16]1[CH:17]=[C:18]([CH2:22][N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[N:19]=[N:20][CH:21]=1)=[CH:7]2
Reactant: OB(O)c1ccc2c(F)cccc2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc3c(F)cccc3c2)cnn1

Procedure:
The title compound, MS: m/e=319.4 (M+H+), was prepared from 5-fluoro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[CH:18][CH:17]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.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>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[CH:18][CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNc1ccc(CN2CCCC2CO)cc1
Temperature: 100 °C
Yield: 59 %

Procedure:
6-Bromo-4-{[4-(2-hydroxymethyl-pyrrolidin-1-ylmethyl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (130 mg, 0.26 mmol) and 2-furyltributyltin (270 mg, 0.76 mmol) and PdCl2(PPh3)2 (30 mg) is mixed in N,N-dimethylformamide (4 mL) and degassed. The solution resulted is heated at 100° C. for 1 hour. After the mixture cooled to room temperature, the N,N-dimethylformamide is removed and the residue is purified through chromatography to afford the title compound (68 mg, 59%). MS (ESI): 444.1 (M+1)+1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Mg].II.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: CSc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSc1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution of 4-bromophenyl methyl sulfide (Aldrich) (3.3 g, 16.4 mmol) in 10 mL of dry diethyl ether is slowly added to a stirred suspension of magnesium turnings (0.44 g, 18.1 mmol) and three crystals of iodine in 10 mL of boiling dry diethyl ether. The reaction is heated at reflux for several hours until almost all the magnesium is consumed. The reaction is cooled to room temperature, and a solution of benzaldehyde (2.0 mL, 19.7 mmol) in 50 mL of dry diethyl ether is added dropwise. The reaction mixture is diluted with ethyl acetate and washed twice with 1N HCl, followed by saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude solid is crystallized from diethyl ether/hexane to give 2.4 g (64%) of 4-methylthiobenzhydrol: melting point 92°-93.5° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([O:14][C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[C:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=2)O1>>[CH3:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11]([O:14][C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])(=[O:13])=[O:12])[CH:6]=2)[C:2]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][C:36]=2[C:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH:46]=2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Product: Cn1cc(-c2ccc(C(F)(F)F)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Intermediate E using perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate and tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE N) as the coupling partners to afford tert-butyl 4-(2-(1-methyl-6-((perfluorophenoxy)sulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as an orange oily solid. m/z (ESI) 726.3 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.26 (d, J=1.5 Hz, 1 H), 7.95 (s, 1 H), 7.77-7.73 (m, 1 H), 7.72 (d, J=8.5 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.63 (d, J=1.9 Hz, 1 H), 7.59 (dd, J=1.8, 8.6 Hz, 1 H), 5.82 (br. s., 1 H), 3.99 (s, 3 H), 3.84 (br. s., 2 H), 3.10 (t, J=5.5 Hz, 2 H), 1.89 (br. s., 2 H), 1.38-1.29 (m, 9 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:8]=1.Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:13][N:29]=[C:14]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: Nc1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCCCl)cc12
Temperature: 3 °C

Procedure:
A mixture of 4-(4-chloro-butoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.54 g, 3.8 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.34 g, 4.0 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.55 g, 3.75 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][N:10]([CH:16]=[O:17])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][N:10]([CH:16]=[O:17])[C:9]=2[CH:8]=[C:7]([N+:18]([O-:20])=[O:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1OCCCN2C=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1OCCCN2C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound 9-formyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylic acid methyl ester (705 mg, 3 mmol) was dissolved in concentrated sulfuric acid (30 mL) and the resulting deep blue solution cooled to 0° C. in an ice bath. It was then treated with 90% fuming nitric acid dropwise (1.5 mL), allowed to warm up to room temperature and stirred for additional 2 hours. The reaction mixture was then carefully poured over 500 mL of ice and the pink precipitate was filtered at room temperature, washed thoroughly with water and dried in vacuo. The crude product was recrystallized from boiling acetonitrile. Yield 702 mg (83%) light yellow crystals, M-280.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)CN
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (2 g, 7.8 mmol) in DCM (40 mL) was added pyridine (1.9 mL, 23.5 mmol) followed by isobutylamine (1.56 mL, 15.7 mmol) and the reaction was stirred at room temperature for 16 hours. 1M aqueous HCl was added and the reaction extracted with DCM, filtered through a phase separator and concentrated to give 4-bromo-N-isobutyl-benzenesulfonamide (1.99 g). LCMS (m/z, Method A) ES+ 294[M+1]+
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)[N:15]=2)[CH:18]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(C(F)(F)F)cc3)cn2c1

Procedure:
24 g (0.077 mole) of 1-bromo-2-(4-trifluoromethylphenyl)-2-ethanone, 8.4 g (0.077 mole) of 2-amino-5-methylpyridine and 13 g of sodium bicarbonate are mixed in 210 ml of 95% strength ethanol, and this suspension is heated under reflux until the evolution of gas has ceased. The solvent is then evaporated off under reduced pressure and the evaporation residue is taken up with water and dichloromethane. The organic phase is decanted and dried over magnesium sulphate, and the solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+]>O1CCCC1>[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of lithium aluminum hydride (0.88 g, 23 mmol) in tetrahydrofuran (50 mL) was added dropwise a solution of Example 59 (1.03 g, 6 mmol) in tetrahydrofuran (10 mL) and the mixture was heated to reflux for about 2 hours. The mixture was cooled to about 0° C. and saturated aqueous sodium hydroxide (3.5 mL) was added dropwise. After stirring for about 10 minutes at room temperature, the mixture was filtered, the filter cake was washed with tetrahydrofuran and the combined filtrates were dried (Na2SO4), filtered and concentrated under vacuum to provide the desired product. 1H NMR (500 MHz, CDCl3): δ 1.10 (m, 1H), 1.60-2.00 (m, 4H), 2.10 (m, 2H), 2.28 (s, 3H), 2.65 (m, 1H), 2.82 (m, 1H), 3.57 (dd, J=8, 14 Hz, 1H), 3.63 (dd, J=8, 14 Hz, 1H), 3.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[O:10]1[C:14]2([CH2:19][CH2:18][CH:17](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:15]2)OCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:17]1[CH2:18][CH2:19][C:14](=[O:10])[CH2:15][CH2:16]1
Reactant: COc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Product: COc1cccc(OC2CCC(=O)CC2)c1
Yield: 57 %

Procedure:
3-methoxy-phenol was reacted with toluene-4-sulphonic acid-1,4-dioxa-spiro[4.5]dec-8-yl ester corresponding to the conditions described in Example 16, step 1. The crude product was subjected, without purification, to an acetal cleavage corresponding to the conditions described in Example 16, step 2. The ketone obtained was purified with diisopropyl ether on a silica gel column. Compound (33) was obtained in a yield of 57% theoretical.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:20][C:19](=[O:21])O[C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:35])=O.O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C>[Cl:35][C:4]1[C:3]2[S:20][C:19](=[O:21])[NH:1][C:2]=2[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(SCc2cccc(F)c2F)nc2oc(=O)sc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: O=c1[nH]c2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred suspension of 7-amino-5-[[(2,3-difluorophenyl)methyl]thio][1,3]oxathiolo[5,4-d]pyrimidin-2-one (5.03 g) and benzyltrimethylammonium chloride (2.58 g) in acetonitrile (25 ml) at 50° C., was first added N,N-diethylaniline (2.46 g) followed by acetonitrile (5 ml), and then phosphorus oxychloride (7.41 g) followed by acetonitrile (5 ml). The reaction mixture was heated to reflux and maintained at this temperature for 36 hours, before cooling to ambient temperature and adding to water (25 ml) at 50° C. with stirring over 30 minutes. An additional acetonitrile (5 ml) rinse of the reaction vessel was added to the drown-out mixture, before heating to 75° C. and slowly cooling to 25° C. at <0.5° C./min. The resulting mixture was held at 25° C. for 30 minutes and then collected by filtration, washing four times with water (25 ml), to afford the title compound as an off-white solid (3.5 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:11].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:27]2[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)=[O:11])=[C:13]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH:14]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 493 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ 8.95-6.75 (m, 8H), 4.95-2.85 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][C:11]=2[CH3:20])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C.[Zn]>[NH2:17][C:13]1[CH:12]=[C:11]([CH3:20])[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:15]([CH3:16])[CH:14]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1NC(=O)CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1NC(=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Zinc dust (10 g) was added in portions over 10 minutes to 2-cyclopentyl-N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (1.45 g) in tetrahydrofuran (40 mL) and acetic acid (10 mL) cooled to 0° C. The reaction mixture was stirred 2 hours at 25° C., neutralized with solid sodium carbonate and filtered through silica (50 g), which was washed with ethyl acetate (200 mL). The organic phase was concentrated in vacuo to furnish 1.15 g (89% yield) of the title compound as a light orange solid. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.96 (s, 6H), 2.22 (m, 1H), 2.23 (d, 2H), 4.81 (b, 2H), 6.23 (s, 2H), 8.74 (s, 1H).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:21]1[CH:29]=[CH:28][C:24](C(O)=O)=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:24]1[CH:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=1)[CH3:4])#[N:2]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCCCc1ccc(C(=O)N[C@@H](C)C#N)cc1
Yield: 42.9 %

Procedure:
General procedure D was used to deprotect 2.8 mmols of 4 and immediately couple to 2.8 mmols of 2 using general procedure F. The product was purified using column chromatography using a solvent system of ethyl acetate and hexanes (1:3, Rf=0.5) to yield 0.340 g (1.2 mmols) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.2, 2H), 7.23 (d, J=7.6, 2H), 6.75 (s, 1H), 5.27-5.06 (m, 1H), 2.71-2.55 (m, 2H), 1.64 (d, J=7.2, 2H), 1.61-1.53 (m, 1H), 1.35-1.13 (m, 10H), 0.87 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 166.56, 147.99, 129.93, 128.81, 128.62, 127.18, 127.03, 119.40, 52.73, 48.54, 36.23, 35.86, 31.84, 31.22, 31.15, 29.41, 29.22, 22.64, 19.60, 18.71, 14.11.