Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1C=NC=CC=1)[CH2:4][CH2:3]2.Cl.Br[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Brc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccncc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 4-bromopyridine hydrochloride (0.018 g, 0.091 mmol) was used in place of 3-bromopyridine, and an additional 1.2 equivalents of sodium tert-butoxide, 2.0M solution in THF (for a total of 5.6 equivalents, 0.212 mL, 0.424 mmol) was employed. The product was isolated after reverse phase preparative HPLC purification using Prep HPLC Method 7 as a beige solid (74 mg, 54% yield) bis TFA salt. LCMS: m/e 650.4 (M+H)+, 3.85 min (method 16). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.19-7.97 (m, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.06 (br. s., 2H), 5.28 (d, J=4.6 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 3.96-3.81 (m, 2H), 3.31-3.19 (m, 2H), 2.88-2.76 (m, 1H), 2.18-2.03 (m, 3H), 1.97 (dd, J=10.4, 6.4 Hz, 3H), 1.83 (d, J=12.5 Hz, 1H), 1.72 (s, 3H), 1.68 (br. s., 1H), 1.66-1.45 (m, 7H), 1.44-1.28 (m, 5H), 1.24 (d, J=8.2 Hz, 1H), 1.18-1.11 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[Cl:26]C1C=CC(C=O)=CC=1>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][CH:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:26])=[CH:20][CH:19]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=Cc1ccc(Cl)cc1
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1

Procedure:
Compound C-4 was prepared in analogy to compound C by using 4-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde without chiral SFC separation of dihydropyrimidine intermediate in Scheme 1-1.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[NH:23][C:24]([NH:26][C:27]([O:29][CH3:30])=[O:28])=[S:25].[OH-].[Ca+2].[OH-].S(OC)(O[CH3:37])=O>CN(C)C=O.O>[NH:1]=[C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]1[NH:23][C:24](=[N:26][C:27]([O:29][CH3:30])=[O:28])[S:25][CH3:37]
Reactant: COS(=O)OC
Reactant: COC(=O)NC(=S)NC1C(=N)C=C(C(=O)c2ccccc2)C=C1Cc1ccccc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(NC1C(=N)C=C(C(=O)c2ccccc2)C=C1Cc1ccccc1)SC
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-5-benzoylbenzene (4.33 g.; 0.01 mol) in dimethylformamide (50 ml.) and water (5 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at 30° C. for 2 hours and to it there is added dimethyl sulfite (1.1 g.; 0.01 mol). The mixture is stirred at room temperature for 3 hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-5-benzoylbenzene.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(Cc4ccccc4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20FN5O2, 417.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:17]([C:13]2[CH:12]=[C:11]([N+:8]([O-:10])=[O:9])[CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccnc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2cccnc2)c1
Temperature: 50 °C
Yield: 76.6 %

Procedure:
To a stirred solution of 3-aminopyridine (2 g, 21.3 mmol) in pyridine (100 ml) was added 3-nitrobenzene sulphonyl chloride (4.43 g, 20 mmol) and the mixture was heated to 50° C. for 3 hours. After cooling it was partitioned between ethyl acetate and water and the organic washed with water (×2) and half saturated aqueous sodium chloride solution, separated, dried and evaporated to give a crude yield of 4.96 g. It was then triturated with dichloromethane and sonicated for 0.25 hours before being filtered and dried to give the product as a pink solid (4.279 g, 72%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH2:20][CH2:19]2.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:13])[CH2:19][CH2:20][CH2:21]2)=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1NCCC2
Reactant: O=C(O)CSc1ncccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc2c1N(C(=O)CSc1ncccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 33 %

Procedure:
To a solution of (3-chloro-pyridin-2-ylsulfanyl)-acetic acid (19, 0.27 g, 1.3 mmol) in 12 mL of dry THF at 0° C. was added neat 8-methyl-1,2,3,4-tetrahydroquinolin (0.20 g, 1.3 mmol) followed by addition of DMAP (0.19 g, 1.6 mmol) and EDCI (0.31 g, 1.6 mmol). The reaction was stirred for 20 h at room temperature under N2. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with H2O, 10% citric acid, NaHCO3 (saturated), brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (hexanes/EtOAc) to give 0.15 g (33% yield) of the target 20 as an off-white solid. MS (APCI) m/z: 333.1 (100%, [M+H]+, 186.0 (35%, [M−147+H]+; HPLC purity: 100%; Anal. Calcd. for C17H17ClN2OS: C, 61.34; H, 5.15; N, 8.42; Cl, 10.65; S, 9.63. Found: C, 61.04; H, 5.28; N, 8.36; Cl. 10.78; S, 9.68.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]2[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH3:23])[CH2:17]2)[CH3:15])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:48]3[CH:47]=[CH:46][C:45]([N:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[CH:3]=[C:4]([O:13][C@@H:14]([C@@H:16]3[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH3:23])[CH2:17]3)[CH3:15])[C:5]=12)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C#N)c34)CC2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile (91.0 mg, 0.188 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (86.5 mg, 0.282 mmol), cesium carbonate (184 mg, 0.565 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (21.8 mg, 0.0188 mmol) was added and the solution was heated at 100° C. for 45 minutes. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to afford tert-butyl 4-(4-(3-cyano-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C@@H:11](O)[CH2:10][C@H:9]2[C:14]([N:16]2[CH2:21][CH2:20][C:19]([CH2:28][N:29]3[C:33]([CH3:35])([CH3:34])[CH2:32][O:31][C:30]3=[O:36])([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.[CH3:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])(=[O:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@H:9]([C:14]([N:16]3[CH2:17][CH2:18][C:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)([CH2:28][N:29]4[C:33]([CH3:34])([CH3:35])[CH2:32][O:31][C:30]4=[O:36])[CH2:20][CH2:21]3)=[O:15])[CH2:10][C@@H:11]([N:38]([CH3:37])[S:39]([C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=3[N+:51]([O-:53])=[O:52])(=[O:41])=[O:40])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@@H]2C[C@H](O)C[C@H]2c2ccc(Cl)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CN([C@@H]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar was charged with 0.103 g (0.20 mmol) of the product of Step F, 0.073 g (0.28 mmol) of N-methyl-2,4-dinitrobenzenesulfonamide and 0.157 g (0.60 mmol) of triphenylphosphine. The solids were dissolved in 2 mL of benzene, and the atmosphere in the flask was evacuated and purged with nitrogen. The reaction mixture was stirred and cooled to 0° C. with an external ice-water bath and then 95 μL (0.60 mmol) of diethyl azodicarboxylate was added. The reaction mixture was allowed to warm to room temperature and was stirred an additional 1 h at which point TLC analysis (75% ethyl acetate-hexanes) indicated consumption of the starting material. The reaction mixture was then evaporated in vacuo and the residue was purified on a Biotage Flash 40i chromatography apparatus (40 g Flash 40S silica gel cartridge) eluted with 50% ethyl acetate-hexanes. Evaporation of the purified fractions and drying in vacuo afforded the title compound as an amorphous yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C1COCC1>[Pd].CO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)cc1NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of Example 28A in 1:1 THF:methanol (40 mL) was treated with 10% palladium on carbon (800 mg), stirred under hydrogen (1 atm) for one hour, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH3:38]>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH:32]4[CH2:36][CH2:35][CH2:34][N:33]4[CH2:37][CH3:38])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCN1CCCC1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (23.4 g, 0.06 mol) was added portionwise to a well stirred mixture of aqueous sodium carbonate (60 g in 600 ml water) and 2-aminomethyl-1 ethyl pyrrolidine (7.8 g, 0.06 mol) in chloroform (600 ml) at about 10° C. The ice bath used for cooling was removed and, after 11/2 hours, the mixture was filtered. The chloroform layer was separated and dried (MgSO4). Concentration under reduced pressure caused precipitation of a solid, which was collected by filtration and dried. Recrystallisation from ethanol gave the title compound (10.5 g), melting point 200°-201.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:23](=[O:24])[N:22]([CH3:25])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:16]2[N:17]=[CH:18][C:13]3[CH:12]=[C:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[C:23](=[O:24])[N:22]([CH3:25])[C:14]=3[N:15]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(S(C)=O)nc21
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(Nc3ccc(Cl)cc3)nc21
Temperature: 25 °C

Procedure:
A mixture of 6-(4-chlorophenylsulfonyl)-8-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (1 eq) and 4-chloroaniline (1.5 eq) in toluene was refluxed overnight. After completion of the reaction (monitored by TLC) the reaction mixture was cooled to ambient temperature. The solid separated, was filtered, washed with hexane, and dried to afford the desired compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][NH2:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.OO.[O-]Cl.[Na+]>O.CO>[CH2:9]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2][N:1]=[N:10]1
Reactant: NCC1(CN)CCOCC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: O
Product: C1CC2(CCO1)CN=NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
C-(4-Aminomethyl-tetrahydro-pyran-4-yl)-methylamine (1.0 g) was taken up in a mixture of H2O (10 mL) and MeOH (2.5 mL), and cooled in an ice bath. Simultaneously, H2O2 (4.8 mL of a 30% solution, 6 equiv.) and NaClO (12.4 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred overnight at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure yielded 380 mg of a clear, light-yellow liquid containing 85% of the anticipated product and 15% of the diamine starting material. This material was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 1.49 (t, 4H), 3.65 (t, 4H), 4.28 (s, 4H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[OH:11][C@@H:12]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:29])[CH2:15]1)[CH3:13].[Cl:30][C:31]1[N:36]=[C:35](S(C)(=O)=O)[C:34]2[N:41]([CH:44]([F:46])[F:45])[CH:42]=[N:43][C:33]=2[CH:32]=1>CN(C=O)C>[Cl:30][C:31]1[N:36]=[C:35]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:34]2[N:41]([CH:44]([F:45])[F:46])[CH:42]=[N:43][C:33]=2[CH:32]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc2ncn(C(F)F)c12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C(F)F)c34)CC2=O)cc1
Reaction time: 0.17 h

Procedure:
Under Ar, NaHMDS (1.0 M in THF, 0.96 mL, 0.96 mmol) was added over 30 s to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (255 mg, 0.968 mmol) in DMF (3 mL). After stirring 10 min, the resulting mixture was added over ca. 45 s to a cooled (−20° C.) solution of 6-chloro-3-(difluoromethyl)-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine (215 mg, 0.763 mmol) in DMF (3 mL). After stifling 15 min, the reaction was quenched with saturated NH4Cl (3 mL) and was diluted with EtOAc (20 mL) and water (20 mL). The phases were separated, and the organic layer was washed with water (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (20-45% acetone in hexanes) to provide (R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H24ClF2N4O3: 465.2; found: 464.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]2[C:10]([C:11](=[O:15])[C:12]=1[O:13][CH3:14])=[C:9]([C:16]#[N:17])[CH:8]=[CH:7][CH:6]=2.C(O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:1]([O:2][C:3]1[C:4](=[O:18])[C:5]2[C:10]([C:11](=[O:15])[C:12]=1[O:13][CH2:14][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[C:9]([C:16]#[N:17])[CH:8]=[CH:7][CH:6]=2)[C:3]1[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1
Reactant: OCc1ccccc1
Reactant: COC1=C(OC)C(=O)c2c(C#N)cccc2C1=O
Solvent: C1CCOC1
Product: N#Cc1cccc2c1C(=O)C(OCc1ccccc1)=C(OCc1ccccc1)C2=O
Reaction time: 0.33 h

Procedure:
14b From Example 9 (972 mg, 4 mmol) is dissolved in tetrahydrofuran (100 ml) containing benzyl alcohol (8 ml) and the tetrahydrofuran (40 ml) is distilled off. The remaining solution is cooled to 15° and sodium hydride (5 mg) with 3 A molecular sieve (2 g) is added. The resulting mixture is stirred at 15°-20° for 20 minutes. The mixture is filtered through a celite bed, the filtrate concentrated to dryness and the residue crystallized from isopropanol giving 1.01 g (64%) of 23 with mp 118°-121°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1COCC1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=S)=[CH:21][CH:20]=1>[Cu](I)I.C(N(CC)CC)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[O:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2nc(Nc3ccc(Cl)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a mixture of methyl 3-amino-2-hydroxybenzoate (700 mg) and THF (21 mL) was added 4-chlorophenylisothiocyanate (717 mg), followed by stirring at room temperature overnight. To the reaction mixture were sequentially added copper iodide (0.87 g) and triethylamine (641 μL), followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and methanol was added thereto, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (20 mL), the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and then triturated with n-hexane-ethyl acetate (10:1, 11 mL) to obtain methyl 2-[(4-chlorophenyl)amino]-1,3-benzoxazole-7-carboxylate (270 mg) as a pale yellow solid.
Reaction SMILES: C([N:4]1[CH2:8][C@@H:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[C@H:6]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][C@H:6]3[C@H:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)[CH2:8][NH:4][CH2:5]3)[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: C=CCN1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: Fc1ccc(C2CCN(C[C@@H]3CNC[C@H]3c3ccsc3)CC2)cc1

Procedure:
A mixture of 1.2 g (3.2 mmol) of 1-Allyl-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine and 0.19 g (0.2 mmol) of Wilkinson's catalyst ([Rh(PPh)3Cl] in 20 mL of an 85% solution of CH3CN in water in a flask fitted with a short path distillation head and an addition funnel for added solvent was heated to reflux. As solvent is azeotroped off, more is added to maintain the original concentration. After stirring at reflux for 4 h, the reaction mixture was concentrated. To the residue was added 3 mL of 2 N HCl and this mixture was partitioned between EtOAc and water. The aqueous fraction was washed with EtOAc and was then made basic with 2 N NaOH solution. The aqueous fraction was then extracted with EtOAc. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification. Mass Spectrum (CI) m/e=345 (M+1)
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].C1(O)C=CC=CC=1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:14]3[S:15][C:16]4[C:21]([N:13]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)[C:3]=2[N:11]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Nc1nc2cccnc2s1
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc2ncnc(Nc3nc4cccnc4s3)c2n1
Yield: 49.3 %

Procedure:
4,6-Dichloro-pyrido[3,2-d]pyrimidine (100 mg; 0.503 mmol) and 76 mg (0.503 mmol) of thiazolo[5,4-b]pyridin-2-yl-amine in 0.3 mol of phenol were heated at 140° C. for 2 hours with stirring. Ethyl acetate was added to the reaction solution and the resulting solid was purified by a thin layer silica gel column chromatography (chloroform:methanol=10:1) to give 78 mg (yield: 45%) of (6-chloro-pyrido[3,2-d]pyrimidin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine as a yellow solid.