Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)CCC.Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:6]3[CH:7]=[CH:8][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=[O:13])=[O:14])=[CH:10][CH:11]=3)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCCOC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCOC)cc3)cc3ccccc23)CC1
Yield: 66 %

Procedure:
(4-Tributylstannylphenyl) (3-methoxypropyl)sulfone (1.70 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.93 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.20 g) in xylene in nitrogen atmosphere for 1 day. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate and adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.87 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:28]3[S:29][C:25]([Cl:24])=[CH:26][CH:27]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ccc(Cl)s1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)s3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R3=Me) and 5-chloro-thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([NH:23][C@@H:24]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25](O)=[O:26])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:8]=[C:7]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:6]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([NH:23][C@H:24]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([N:2]([CH3:3])[CH3:1])=[O:26])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:8]=[C:7]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:6]=1
Reactant: CNC
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)CC4)nc(N)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@H](Cc3ccccc3)C(=O)N(C)C)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from dimethylamine (2.0 M solution in THF), (S)-2-(7-(2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-carboxamido)-3-phenylpropanoic acid, triethylamine, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. Analytic LCMS (M+H)+: m/z=543.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 42 °C

Procedure:
78.25 g (0.5mol) of 4-chlorobenzoic acid were suspended in 200 ml of methylene chloride, followed by the addition with stirring at room temperature of 33.5 g (0.55 mol) of 98% nitric acid. The mixture was heated with stirring to boiling temperature, followed by the dropwise addition over a period of 1 hour at that temperature of 63.5 g of 100% sulphuric acid. After cooling to 42° C., the mixture was stirred for 2 hours at that temperature. The reaction mixture was then poured onto 300 ml of water, and the methylene chloride subsequently distilled off. The residual suspension was filtered, the residue washed with water and dried at 90° C., giving 98.4 g (97.3% of the theoretical yield) of 4-chloro-3-nitrobenzoic acid melting at 182.9° to 184.0° C. with a purity of 99.5%. The content of unreacted 4-chlorobenzoic acid amounted to only about 0.1%.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH:11]=[C:10]1[O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([NH2:37])(=[O:36])=[O:35]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:20][C:10]1[C:9](=[O:8])[C:18]2[C:13]([C:12](=[N:37][S:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH:11]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:28])([CH3:27])[CH3:26]
Reactant: NS(=O)(=O)c1cccs1
Reactant: CC(C)(C)OC(=O)COC1=CC(=O)c2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
triethyl amine (0.12 ml, 0.88 mmol) was added in the mixture of tert-Butyl 2-(1,4-dioxo-1,4-dihydronaphthalen-2-yloxy)acetate (7c, 0.115 g, 0.4 mmol) and thiophene-2-sulfonamide (0.078 g, 0.48 mmol) in anhydrous DCM (4 ml), followed by adding TiCl4.2THF. The reaction mixture was heated with μW at 60° C. for 20 min. and poured into EtOAC, then filtered with celite. The filtrate was concentrated under reduce pressure and purified by flash chromatography to give compound 8d as a yellow solid, 22%, m.p.=153-155° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:38](=[O:41])[CH2:39][CH3:40])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by propanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 108 mg, 63%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz) 7.57-7.76 (2 H, m), 7.30 (2 H, dd, J=8.46, 5.68 Hz, 7.15 (2 H, t, J=8.84 Hz), 6.52 (1 H, s), 5.05-5.43 (2 H, m), 4.46-4.62 (0.5 H, m), 4.38 (1 H, d, J=12.63 Hz), 3.85-4.00 (3.5 H, m), 3.05-3.23 (1 H, m), 2.77 (2 H, s), 2.65 (1 H, s), 2.55-2.63 (1 H, m), 2.39 (1 H, q, J=7.33 Hz), 2.29 (1 H, q, J=7.33 Hz), 1.41-1.80 (4 H, m), 0.98 (3 H, q, J=7.49 Hz); m/z (APCI+) for C26H30N5O2F 464.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](O)=[O:34]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:33]([C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]=2[OH:22])=[O:34])[CH2:13][C@H:12]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: O=C(N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C26H24N3O5 [(M+H)+] 458, obsd. 458.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH3:12]>>[CH2:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:12]
Reactant: CCBr
Reactant: c1ccc2[nH]ccc2c1
Product: CCn1ccc2ccccc21

Procedure:
The title compound was prepared according to general procedure A described in Scheme 1 from indole and bromoethane. The crude material was used directly without further purification
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2ccnc2)c(Br)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-Bromo-4-fluorobenzonitrile (10.0 g, 50 mmol, 1 eq) and imidazole (5.1 g, 75 mmol, 1.5 eq) are dissolved in dimethylformamide (100 ml) and carefully admixed with sodium hydride (60% in mineral oil, 3.0 g, 75 mmol, 1.5 eq) under nitrogen at room temperature. The mixture is stirred at 100° C. for 4 hours. After cooling to room temperature, water (10 ml) is added and the mixture is evaporated to dryness. The residue is washed with water and petroleum ether and purified by column chromatography (silica gel, methyl tert-butyl ether/ethyl acetate gradient).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[N:27]1([C:31]([C:33]2[S:37][C:36](Cl)=[N:35][CH:34]=2)=[O:32])[CH2:30][CH2:29][CH2:28]1>C(#N)C>[N:27]1([C:31]([C:33]2[S:37][C:36]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:35][CH:34]=2)=[O:32])[CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1cnc(Cl)s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cc(Oc2ncc(C(=O)N3CCC3)s2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
Cesium carbonate (488 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (187 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole (152 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 160° in a Biotage Initiator Microwave for 2 hours. The mixture was cooled to RT and pressure, poured onto water (75 mL) then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica eluting with ethyl acetate, to give the desired compound (142 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 2.4 (m, 2H), 3.7 (s, 3H), 4.1-4.4 (m, 4H), 4.5 (m, 1H), 6.75 (s, 1H), 6.9 (s, 1H), 7.2 (s, 1H), 7.25 (d, 1H), 7.4 (s, 1H) and 8.95 (s, 1H). m/z 442 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]=O)[CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4].[C:19]1([CH3:25])[CH:24]=CC=C[CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]=[CH:5][C:3]([O:4][C:19]([CH3:20])([CH3:24])[CH3:25])=[O:2])[CH:10]=[C:9]([Cl:18])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(CCC=O)cc(Cl)cc2[nH]1
Reactant: Cc1ccccc1
Product: COC(=O)c1cc2c(CCC=CC(=O)OC(C)(C)C)cc(Cl)cc2[nH]1
Yield: 82 %

Procedure:
A mixture of 6-chloro-4-(3-oxopropyl)indole-2-carboxylic acid methyl ester (12.0 g, 45.2 mmol) and (tert-butoxycarbonylmethylene)triphenylenephosphorane (18.7 g, 49.7 mmol)in toluene (500 mL) was refluxed for 1 h and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/toluene to give 12.21 g of the title compound (82%): 1H NMR (CDCl3) δ9.03 (bs, 1H), 7.29 (d, 1H, J=1.7 Hz), 7.20 (d, 1H, J=2.0 Hz), 6.95 (d, 1H, J=2.0 Hz), 6.92 (dt, 1H, J=15.5, 6.6 Hz), 5.80 (dt, 1H, J=15.5, 1.7 Hz), 3.96 (s, 3H), 3.01 (dd, 2H, J=8.6, 7.3 Hz), 2.59 (dd, 2H, J=14.5, 6.6 Hz), 1.49 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7](=[O:24])[O:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([CH3:22])=[C:11]([Cl:23])[CH:10]=2)C.[Br:26]N1C(=O)CCC1=O.Cl>C(OCC)(=O)C.C(O)(=O)C>[Br:26][CH2:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[Cl:23])[O:8][C:7](=[O:24])[C:6]([CH2:5][C:4]([OH:3])=[O:25])=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc(C)c(Cl)cc2oc1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)c2cc(CBr)c(Cl)cc2oc1=O

Procedure:
A solution of ethyl(7-chloro-6-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)acetate (3.5 g) in ethyl acetate (50 ml) was combined with N-bromosuccinimide (2.1 g) and 2,2′-azoisobutyronitrile (48.3 mg), and heated under reflux for 1 hour. After cooling, the reaction solution was washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate-hexane=1:4) to obtain the crude crystal (approximately 2.6 g) of ethyl 2-[6-(bromomethyl)-7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl]acetate. The crude crystal was dissolved in acetic acid (50 ml) and concentrated hydrochloric acid (25 ml), and heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to obtain a crude crystal (1.78 g, yield: 44%) of the title compound. The compound was used in the next reaction without further purification. NMR (CDCl3) δ: 3.43 (2H, s), 4.58 (2H, s), 7.11 (1H, s), 7.20-7.30 (2H, m), 7.48 (1H, s), 7.50-7.65 (3H, m).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([C:11]1([CH2:51][CH2:52][CH2:53][CH3:54])[C:23]2[CH:22]=[C:21]([CH2:24][C:25](C)(O)C#C)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][C:14]([C:30]#[C:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:34][CH:33]=1)=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH3:10]>C1(C)C=CC=CC=1.CC(O)C>[CH2:51]([C:11]1([CH2:7][CH2:8][CH2:9][CH3:10])[C:12]2[CH:13]=[C:14]([C:30]#[C:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:37]=3)[CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=2)[CH2:52][CH2:53][CH3:54]
Reactant: C#CC(C)(O)Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#Cc3ccc(N(CCCCCC)CCCCCC)cc3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#Cc3ccc(N(CCCCCC)CCCCCC)cc3)ccc1-2
Yield: 87 %

Procedure:
Potash powder (0.07 g) is added to a solution of 5a (0.798 g, 1.24 mmol) in 8.75 mL of toluene/i-PrOH (6/1). The mixture is heated in a reverse-flow boiler for 1 h. After cooling, the potash is filtered and the solvents are evaporated. The raw product is purified by silica gel column chromatography (heptane/CH2Cl2 90:10) to yield 0.632 g (87%) of 5b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[N+:27]([O-])=O)(=[O:16])=[O:15])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.Cl[Sn]Cl>Cl.CCO>[NH2:27][C:18]1[CH:19]=[C:20]([C:23]([F:25])([F:24])[F:26])[CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:15])=[O:16]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2N)c2ncccc12
Yield: 94.6 %

Procedure:
In a similar fashion using route 2 general procedure 4 N-(5-methoxy-quinolin-8-yl)-2-nitro-4-trifluoromethyl-benzenesulfonamide 587 (500 mg, 1.17 mmol), SnCl2 (0.9 g, 4.6 mmol), 6N HCl (2 drops) and EtOH (10 ml) at 85° C. for 48 h gave the title compound (440 mg, 92%) which was used in the next step without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[N:9]=[C:8]([C:49]([F:52])([F:51])[F:50])[N:7]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.O>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([C:49]([F:51])([F:50])[F:52])[N:9]=[C:10]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:11]=1
Reactant: CC(=O)OCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reaction time: 0.75 h

Procedure:
To a solution of [6-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl)carbonyl]-2-(trifluoromethyl)pyrimidin-4-yl]methyl acetate (0.85 g, 1.15 mmol, from Step D) in THF (16 mL) at room temperature was added a solution of lithium hydroxide, monohydrate (0.072 g, 1.7 mmol) in water (4 mL). The reaction was stirred for 45 minutes, then was neutralized by the addition of 1N HCl and the product was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, decanted and concentrated to afford a yellow foam, which was used without further purification. Yield: 0.72 g (90%); LC-MS: 697.2 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.86 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.92 (s, 1H), 7.42 (d, 1H), 6.81 (d, 1H), 5.68 (s, 2H), 4.92 (s, 2H), 4.28-4.17 (m, 1H), 3.89-3.71 (m, 3H), 3.71-3.61 (m, 2H), 3.55 (dd, 2H), 3.47-3.34 (m, 3H), 3.33-3.21 (m, 1H), 2.68-2.53 (m, 1H), 1.93-1.68 (m, 2H), 1.60-1.41 (m, 2H), 0.92 (dd, 2H), −0.06 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4].Cl.[Cl:43]CCl>O1CCOCC1>[ClH:43].[CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCSc1ccccc1)CCCC3
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.50 g, 0.86 mmol), a 4 M solution of hydrochloric acid in dioxane (5 mL), and dichloromethane (5 mL). The reaction was judged to be complete after stirring at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford an off white solid. The material was recrystallized from acetonitrile to provide 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (0.17 g, 1.30 mmol) as fluffy white needles, m.p. 237-238° C. Analysis. Calculated for C22H28N4S(H2O)1/4 (HCl)2: %C 57.70; %H, 6.71; %N, 12.23. Found %C 57.62; %H, 6.57; %N, 12.41
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:30][OH:31]>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:30][OH:31])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(=O)C(F)(F)F)cc3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C(=NO)C(F)(F)F)cc3)c2)CCOCC1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 69, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α,α,α-trifluoroacetophenone was reacted with hydroxylamine hydrochloride to give 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α,α,α-trifluoroacetophenone oxime in 70% yield, m.p. 131°-133° C.;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[N:3]=1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>C(O)C>[N:10]1[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[C:8]([C:4]2[N:3]=[C:2]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[CH:7]=[CH:6][N:5]=2)[CH:9]=1
Reactant: Clc1ccnc(-c2cnn3ccccc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of 3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 33, 130 mg, 0.56 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (326 mg, 1.63 mmol) in ethanol (5 mL) was heated overnight at 100° C. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was taken up in a mixture of chloroform and water. The aqueous layer was separated and washed with chloroform (×2). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography (dichloromethane to 95:5 dichloromethane/methanol) to give the title compound (150 mg, 68%).