Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]1=[O:38].C(=O)([O-])[O-].[K+].[K+].N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:27]3=[O:38])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: O=C1C(CCCCBr)CCN1Cc1ccccc1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
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: [K+]
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCCC2CCN(Cc3ccccc3)C2=O)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.086 g, 0.29 mmol) and 3-(4-bromobutyl)-1-(phenylmethyl)-2-pyrrolidinone (0.17 g, 0.55 mmol, 1:1 mixture with 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one) in THF (5 ml) was added potassium carbonate (0.08 g, 0.58 mmol) and the mixture heated and stirred at 50° C. for 18 h. The solution was allowed to cool then degassed (sequential evacuation followed by addition of nitrogen×3) and Pd(PPh3)4 (0.09 g, 0.077 mmol) followed by morpholine (0.2 ml, 2.2 mmol) added and the solution stirred at ambient temperature for 18 h. The solution was separated between ethyl acetate and dil HCl and the organics washed with brine, dried and concentrated. Purification of the residues using an aminopropyl SPE (5 g) eluting first with MeOH then 5% AcOH/MeOH yielded the title compound as a yellow oil which crystallised on standing under ether (0.031 g, 22%).
Reaction SMILES: C(O)(=O)C.[BH4-].[Na+].[C:7]1([C@@H:13]([NH:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[C:7]1([C@@H:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 23 °C
Yield: 90 %

Procedure:
Acetic acid (1.0 L) was added to a reactor followed by sodium borohydride (100 g) with cooling between 16-30° C. under nitrogen in NLT 1 hour and mixed for NLT 30 minutes. Acetonitrile (500 mL) was added and mixed for NLT 30 minutes, and the cooled to below 5° C. A solution of (S)-ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8, 269 g) dissolved in acetonitrile (250 mL) was added in NLT 30 minutes, while maintaining the temperature between 2-8° C. and then the reaction mixture was warmed to 22° C., and mixed for NLT 4 hours. The mixture was cooled below 5° C. and quenched with 1.77 L of 25% aqueous sodium hydroxide solution, water (1.3 L) and heptanes (0.75 L) and the pH was adjusted pH to ˜8.0. The organic layer was separated and the aqueous layer was extracted with heptanes (2×0.75 L), and then the combined heptane layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L). The heptane solution was then dried using anhydrous magnesium sulfate and concentrated under vacuum to afford 243.9 g of (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9) as the major isomer.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([OH:16])[CH:9]=1)(C)(C)C.[C:19]1([CH2:25][CH2:26][CH2:27]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:16][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C#N)c(O)c1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CO)cc1OCCCc1ccccc1
Reaction time: 14 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy-benzonitrile from step 2 (50 mg, 0.19 mmol) was dissolved in DMF (1 ml) and treated with phenylpropylbromide (29 μl, 0.19 mmol). Cs2CO3 (68 mg, 0.21 mmol) was then added and the reaction mixture stirred at room temp. for 14 hours. The mixture was filtered and washed with DMF (3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:39][CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN1CCC(N)CC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCN(C)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ1.45 (m, 2H), 1.85 (m, 4H), 2.40 (s, 3H), 2.72 (m, 2H), 3.30 (m, 1H), 5.41 (m, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.05 (m, 4H), 7.29 (m, 3H). LC MS (m/e)=480 (MH+). Rt=1.67 min
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1.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.[Cu]I>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC#CC(=O)c1ccc(C(F)(F)F)cc1
Yield: 37.5 %

Procedure:
To a solution of N-boc-propargylamine (5.0 g, 32.2 mmol) in THF (100 mL) was added 4-trifluoromethylbenzoyl chloride (4.3 mL, 29.3 mmol), PdCl2(PPh3)2 (0.18 g, 0.264 mmol), and CuI (0.17 g, 0.879 mmol). The mixture was allowed to stir for 5 min at rt, at which time freshly distilled triethylamine (5.1 mL, 36.6 mmol) was added. After 30 min the resulting mixture was filtered, concentrated, and purified by flash column chromatography, or FCC, to afford the title compound as a colorless solid (3.6 g, 35%). MS (ESI): mass calcd. for C16H16F3NO3, 327.1; m/z found, 328.2 [M+H]+. 1H NMR (500 MHz, (DMSO) δ 8.26 (d, J=8.04 Hz, 2H), 7.96 (d, J=8.12 Hz, 2H), 7.62-7.54 (m, 1H), 4.14 (d, J=5.53 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:10]3[O:31][CH:30]=[CH:29][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[C:22](=[O:24])[NH:23][C:18]=4[CH:17]=3)[N:14]=2)[CH2:4][CH:3]1[O:32][Si](C(C)(C)C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.ClC1N=C(Cl)C2OC=CC=2N=1.NC1C=CC2OC(C)(C)C(=O)NC=2C=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:10]3[O:31][CH:30]=[CH:29][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[C:22](=[O:24])[NH:23][C:18]=4[CH:17]=3)[N:14]=2)[CH2:4][CH:3]1[OH:32]
Reactant: CC1(C)Oc2ccc(Nc3nc(N4CCCC(N)C(O[Si](C)(C)C(C)(C)C)C4)c4occc4n3)cc2NC1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC1(C)Oc2ccc(N)cc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(Nc3nc(N4CCCC(N)C(O)C4)c4occc4n3)cc2NC1=O
Yield: 35 %

Procedure:
A mixture of 6-(4-(4-amino-3-(tert-butyldimethylsilyloxy)azepan-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.400 g, 0.724 mmol, prepared using F from Preparation #AH.1, O with Boc2O, K, A with 2,4-dichlorofuro[3,2-d]pyrimidine [Arkpharm], B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [ArkPharm] and C) and TBAF (0.378 g, 1.45 mmol) in THF (10 mL) was stirred at about 25° C. for about 4 h. The mixture was concentrated and purified by preparatory HPLC (Table 2, Method t) to give 6-(4-(4-amino-3-hydroxyazepan-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.11 g, 35%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 439 (M+H)+. Syk IC50=B
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](C1NC=CN=1)=[O:29])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl-].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][S:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH3+:64].CCN(CC)CC>CN(C=O)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:29])[NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][S:43][S:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)(=[O:5])[O:3][CH2:1][CH3:2])=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: [NH3+]CCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)NCCOCCOCCOCCCCCCCCCCCSSc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 66 h

Procedure:
A solution of phosphonate 17 (68 mg, 0.14 mmol), amino disulfide 18 (60 mg, 0.13 mmol), and Et3N (35 mL, 0.25 mmol) dissolved in DMF was stirred at 60° C. for 66 h. After concentration of the reaction mixture, the crude residue was purified by column chromatography (hexane/EA=1:1) to afford the disulfide, which contained approximately 20% starting materials. ′H NMR (CDCl3, 500 MHz) δ 8.44 (s, 1H), 8.32 (s, 1H), 8.21 (d, J=9 Hz, 2H), 7.78 (br s, 1H), 7.70 (br s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.07 (br s, 1H), 4.15 (m, 2H), 3.98 (m, 2H), 3.62-3.49 (br m, 10H), 3.45 (m, 2H), 3.32 (m, 2H), 2.78 (t, J=7.5 Hz, 2H), 1.90 (m, 2H), 1.79 (m, 2H), 1.71-1.44 (br m, 4H), 1.40-1.07 (br, 33H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Si:16]([O:23][CH2:24][C:25]1[CH:30]=[C:29](O)[CH:28]=[C:27]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=2)[N:26]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(Cl)(Cl)Cl.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:29]1[CH:28]=[C:27]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=2)[N:26]=[C:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:30]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(O)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(OS(=O)(=O)C(F)(F)F)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.7 ml of trifluoromethanesulfonic anhydride was added to a mixture of 12.9 g of 2-(((tert-butyl(dimethyl)silyl)oxy)methyl)-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-4-ol, 14.2 g of 4-(dimethylamino)pyridine and 290 ml of chloroform at 0° C. The resulting mixture was stirred for 2 hours at room temperature and then diluted with ethyl acetate. The resulting solution was charged with 100 ml of 0.1 mol/l hydrochloric acid at 0° C. The organic layer separated was washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([NH2:9])[N:8]=1)[CH3:2].[SH2:12]>>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:10](=[S:12])[NH2:11])=[C:7]([NH2:9])[N:8]=1)[CH3:2]
Reactant: CCSc1nc(N)c(C#N)s1
Reactant: S
Product: CCSc1nc(N)c(C(N)=S)s1
Yield: 49 %

Procedure:
55.5 parts of 2-ethylmercapto-4-amino-5-cyano-thiazole are reacted with 20 parts of hydrogen sulfide as described in Example 1(a). 32.1 parts of 2-ethylmercapto-4-amino-5-thiocarbamoylthiazole (49% of theory) of melting point 180°-183° C. are obtained.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].CCCCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[CH2:24][CH2:23]2.C(=O)CCC>O1CCCC1>[CH:8](=[C:24]1[CH2:23][C:22]2[C:26](=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[C:25]1=[O:29])[CH2:9][CH2:10][CH3:11]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCC=O
Product: CCCC=C1Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (0.227 mL, 1.62 mmol) in anhydrous tetrahydrofuran (THF, 15 mL) was placed under a nitrogen atmosphere, cooled in an ice bath, and stirred while a 2.0M solution of butyllithium in pentane (0.771 mL, 1.54 mmol) was added dropwise over 2 minutes. The solution was stirred at room temperature for 15 minutes, then cooled in a dry ice-acetone bath and treated dropwise over 3 minutes with a solution of 5-methoxy-1-indanone (250 mg, 1.54 mmol) in THF (2 mL). After stirring at −78° C. for 20 minutes, the reaction mixture was treated with butyraldehyde (0.167 mL, 1.85 mmol). After stirring an additional 26 minutes at −78° C., the reaction mixture was removed from the cooling bath and stirred at room temperature for 90 hours. The reaction mixture was treated with saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc (15 mL). The organic phase was washed with brine (25 ml), dried over MgSO4, filtered, and evaporated under vacuum to an oil (353 mg). The crude product was purified by silica gel chromatography on a Biotage FLASH 12M column (1.2×15 cm), eluting with 7:1 hexanes-EtOAc, to afford 2-butylidene-5-methoxy-1-indanone (205 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[C:12]1([O:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:19](=[O:20])[O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]([O:10][CH3:11])=[N:4][C:5]=1[CH3:9]
Reactant: COc1nc(C)c(C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3-Amino-5,6-dimethyl-2-methoxypyridine(1.52 g, 0.01 mol) and phenylchloroformate(1.56 g, 0.01 mol) were dissolved in dichloromethane and was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(ethylacetate:hexane=1:6) to obtain the titled compound.
Reaction SMILES: FC1C=CC(CN2[C@@H](C)CN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)=CC=1.[F:27][C:28]1[CH:52]=[CH:51][C:31]([CH2:32][N:33]2[CH2:37][C@H:36]([CH3:38])[N:35]([C:39]3[S:40][C:41]([C:45]([O:47]CC)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:50])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][C@H:36]([CH3:38])[N:35]([C:39]3[S:40][C:41]([C:45]([OH:47])=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:50])=[CH:51][CH:52]=1
Reactant: CCOC(=O)c1sc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)nc1C
Agent: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O

Procedure:
Following the procedure as described in Preparation 6, making variations as required to replace (S)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with (S)-ethyl 2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (91%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.08-7.02 (m, 2H), 4.67-4.62 (m 1H), 4.55 (d, J=14.9 Hz, 1H), 4.44 (d, J=14.9 Hz, 1H), 3.58 (t, J=9.0 Hz, 1H), 3.00 (dd, J=9.0, 3.1 Hz, 1H), 2.64 (s, 3H), 1.48 (d, J=6.2 Hz, 3H); (ES+) m/z 349.9 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8](COCC[Si](C)(C)C)[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([NH:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[NH:28]1[CH2:27][CH2:26][CH:25]([NH:24][C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[NH:8][C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)[nH]c1nccc(NC3CCNCC3)c12
Temperature: 75 °C
Yield: 48.9 %

Procedure:
tert-Butyl 4-{6-cyano-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrol-4-ylamino}piperidine-1-carboxylate (80 mg, 0.14 mmol) was dissolved in 1,4-dioxane (0.4 mL) and then treated with 48% HBr(aq)(0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC (5-85% methanol in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as a pale yellow solid (20 mg, 30% over two steps). 1H NMR (DMSO-D6, 400 MHz): 9.08 (s, 1H), 8.83 (s, 1H), 8.20 (d, J=5.9 Hz, 1H), 6.63 (d, J=6.0 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 3.74 (m, 1H), 3.11 (m, 2H), 2.71 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H). LCMS (Method E): RT=2.28 min, M+H+=293.
Reaction SMILES: [F:1][C:2]1[CH:52]=[CH:51][CH:50]=[CH:49][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:52]=[CH:51][CH:50]=[CH:49][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Oc5ccccc5F)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(Oc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-(2-fluorophenoxy)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TFA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated. The product N-[3-(2-fluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide was obtained and purified by reverse phase HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:29].C(N(CC)CC)C>CN(C)C=O.CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=2[CH3:29])[CH2:13][CH2:12]1
Reactant: Cc1ccc([N+](=O)[O-])cc1CCBr
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1CCN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Yield: 76.3 %

Procedure:
A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (2.7 g) in dimethyl formamide (75 mL), 2-(2-bromoethyl)-1-methyl-4-nitrobenzene (3.7 g) in butanone (200 mL) and triethylamine (9.3 mL) was boiled under reflux for 20 h, and the resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/triethylamine 100:4) to give 5-fluoro-3-{1-[2-(2-methyl-5-nitrophenyl)ethyl]piperidin-4-yl}-1H-indole (3.6 g), which subsequently was dissolved in acetic acid (25 ml) followed by the addition of ethanol (75 mL) and platinum oxide (50 mg). The resulting mixture was shaken under 3 atmosphere hydrogen pressure for 3 h at room temperature. The mixture was reduced in vacuo (50 mL), poured onto an ice/water mixture followed by the addition of aqueous ammonia to basic pH. The aqueous phase was extracted with an ethyl acetate/tetrahydrofuran mixture, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:4:4) to give 3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-5-fluoro-1H-indole (1.0 g), which subsequently was dissolved in tetrahydrofuran (45 mL) and triethylamine (1.3 mL) at 5° C. followed by the addition of cyclobutancarbonyl chloride (0.3 g) in tetrahydrofuran (15 mL). The resulting mixture was stirred at 5° C. for 1 h, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:4:4) to give the crude product that was isolated as the oxalate salt from ethyl acetate as a white crystalline compound (0.7 g). Mp 116-125° C. 1H NMR (DMSO-d6): 1.75-1.85 (m, 1H); 1.85-2.05 (m, 3H); 2.05-2.25 (m, 6H); 2.30 (s, 3H); 2.90-3.25 (m, 8H); 3.65 (d, 2H); 6.85-6.95 (m, 1H); 7.10 (d, 1H); 7.25 (s, 1H); 7.30-7.40 (m, 2H); 7.40 (d, 1H); 7.55 (s, 1H); 9.65 (s, 1H); 11.00 (s, 1H). MS m/z: 434 (MH+).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)C1CCCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution 3.0 g (9.7 mmol) of 1-benzylpiperidine-3-carboxylic acid benzyl ester (Example A21) in methanol (20 mL) was added 1N sodium hydroxide (20 mL), and the reaction is stirred at room temperature for 18 hours. The methanol is removed in vacuo and the basic aqueous solution is acidified to pH 4 with 1.0 M hydrochloric acid. After washing with ethyl acetate, the aqueous acid layer is lyophilized. The solid is suspended in methanol (10 mL), stirred for 10 minutes and filtered. The filtrate is evaporated in vacuo to afford the title compound (2.0 g). 1H NMR (200 MHz, DMSO-d6): δ 7.38–7.23 (m, 5H), 3.58 (s, 2H), 2.98–2.40 (m, 3H), 2.30–1.25 (m, 6H).