Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)=[O:14])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>C1COCC1>[N:35]1([C:41]([N:25]2[CH2:24][CH:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:13]([C:11]3[N:12]=[C:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[S:9][CH:10]=3)=[O:14])[CH2:27][CH2:26]2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1ccccc1C1=CCNCC1)c1csc(-c2ccccc2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1C1=CCN(C(=O)N2CCOCC2)CC1)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 170 mg of 2-phenyl-N-[2-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1,3-thiazole-4-carboxamide hydrochloride in 7 ml of THF was added 0.30 ml of triethylamine, and 60 μl of 4-morpholinecarbonylchloride was added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction liquid was added 100 ml of water, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A solvent was evaporated under reduced pressure, and the residue was recrystallized from 5 ml of ethanol to obtain 165 mg of N-{2-[1-(4-morpholinylcarbonyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}-2-phenyl-1,3-thiazole-4-carboxamide.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:4]([C:22]1[CH:21]=[CH:20][C:19]([O:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:18][CH:23]=1)([CH3:13])([CH3:5])[CH3:3]
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 70.3 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 2-fluorophenol (63 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, and washed with H2O. The precipitate was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 79 (23 mg, 40% yield) as a tan solid. LC-MS (M+H=307, obsd.=307). 1H NMR (400 MHz, d6-DMSO): δ 11.99 (s, 1H), 8.74 (dd, 1H), 8.50 (dd, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 7.49 (m, 1H), 7.33 (m, 4H), 7.18 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[C:10](=[O:15])[O:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C:18]1([C:21]#[N:22])[CH2:20][CH2:19]1.C(C(CCCC)C([O-])=O)C.[Na+].Cl.[Cl-].[Na+]>O.C(OCC)(=O)C>[C:21]([C:18]1([NH:17][C:10]([C@@H:9]2[CH2:14][C@H:12]([OH:11])[CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15])[CH2:20][CH2:19]1)#[N:22]
Reactant: N#CC1(N)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C(=O)O2
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)NC1(C#N)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 55.1 %

Procedure:
A suspension of tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate 8 (1 g, 4.69 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (743 mg, 6.27 mmol) and sodium 2-ethylhexanoate (1.22 g, 7.12 mmol) in water (7 mL) was stirred for 2 days at 50° C. The reaction was acidified with 1N aqueous hydrogen chloride solution, saturated with sodium chloride and stirred with ethyl acetate for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica using a gradient of methylene chloride to a mixtures of methylene chloride and methanol (v:v 19:1) to yield the amide 9 as an off-white solid (763 mg, 55.1%). MS ISN (m/e): 294.3 (100) [(M−H)]+.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:38]2=[O:52])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:38]2=[O:52])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained as a white powder: 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.17-6.85 (m, 5H), 6.22 (s, 1H), 5.83 (s, 2H), 5.04 (t, 1H), 4.56-4.08 (m, 5H), 3.69 (m, 1H), 1.18 (t, 3H); MS (ES+) m/z 408.1 (M+23).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45][C:46](=[O:49])[CH2:47]Cl)(C)(C)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[K+]>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:49])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 150 ml of 50% aqueous potassium hydroxide solution is cooled to 0° C. At 0° C., 30.12 g (200 mmol) of chloroacetic acid-tert-butyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 10° C. 250 ml of methyl-tert-butyl ether is added, the organic phase is separated, and the aqueous phase is extracted twice with 250 ml of water. The solvent of the combined organic phases is distilled off in a vacuum, and the residue is taken up in 500 ml of ethanol. 40 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is shaken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:23][C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)=[N:28][CH:29]=1>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:23][C:24]2[CH:29]=[N:28][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)=[N:26][CH:25]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: ClCc1cnc(Nc2ccc(Cl)c(Cl)c2)nc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2cnc(Nc3ccc(Cl)c(Cl)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyl)oxy)phenol (0.086 g, 0.381 mmol), Cs2CO3 (0.186 g, 0.572 mmol) and 5-(chloromethyl)-N-(3,4-dichlorophenyl)pyrimidin-2-amine (0.110 g, 0.381 mmol) in DMF (3.8 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography on silica gel using 10-50% ethyl acetate in hexanes. The desired fractions were concentrated to give 5-((4-(tert-butyldimethylsilyloxy)phenoxy)methyl)-N-(3,4-dichlorophenyl)pyrimidin-2-amine as a yellow solid (0.022 g, 12%). LCMS: R.T.=3.73 min; [M+H]+=476.23
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.Cl[Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH3:9][N:10]1[C:14]([Sn:16]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=[N:11]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (1.5 M in cyclohexane) (9.7 mL, 14.6 mmol) was added to a −78° C. solution of 1-methylpyrazole (1 g, 12.2 mmol) in tetrahydrofuran (15 mL). After stirring at −78° C. for 15 min, chloro-tri-n-butylstannane (3.9 mL, 14.6 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-100 ethyl acetate/hexane afforded 1-methyl-5-(tributylstannyl)-1H-pyrazole.
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C([O-])(O)=O.[Na+]>C1COCC1.Cl>[CH:14]1[CH:13]=[N:12][CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH:2]=[O:1])[CH:15]=1
Reactant: c1cncc(CCCC2OCCCO2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCCc1cccnc1
Yield: 94.5 %

Procedure:
A solution of 1.5 g (7.8 mmol) of acetal 157 in 10.0 mL of THF and 10.0 mL of 4N HCl was stirred overnight at room temperature and was then neutralized by the slow addition of solid NaHCO3. The reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to yield 1.1 g of the aldehyde 158. 1H NMR consistent with structure.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[CH2:21]([O:23][C:24]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]([NH2:31])[CH:25]=1)[CH3:22]>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25]2[C:24]([O:23][CH2:21][CH3:22])=[N:29][C:28]([NH2:30])=[N:27][C:26]=2[NH:31][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CCOc1cc(N)nc(N)n1
Solvent: CC(C)O
Product: CCOc1nc(N)nc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2

Procedure:
270 mg (1 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione and 170 mg (1.1 mmol) of 6-ethoxypyrimidine-2,4-diamine are dissolved in 5 ml of isopropanol and heated under reflux under argon for 2 days. The mixture is then concentrated and the residue is purified by preparative HPLC. 230 mg (56% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH2:35][CH:36]([NH2:42])[C:37]1[CH:41]=[CH:40][S:39][CH:38]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH2:35][CH:36]([NH:42][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:37]1[CH:41]=[CH:40][S:39][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccsc1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5ccsc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and (3-amino-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester (from Example 69 supra) (412 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-thiophen-3-yl-propyl)-carbamic acid tert-butyl ester. (Yield 400 mg).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]=[C:14]2[CH2:27][C:28]([O:30]CC)=O)(=[O:6])[O:4][CH3:5].[Al]([NH2:36])(C)C.O.Cl>C1(C)C=CC=CC=1.C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]=[C:14]2[CH2:27][C:28]([NH2:36])=[O:30])(=[O:6])[O:4][CH3:5]
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccc(OCCCP(=O)(OC)OC)cc12
Reactant: C[Al](C)N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1)OC
Temperature: 50 °C
Yield: 80 %

Procedure:
[3-[[3-(2-Ethoxy-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (590 mg, 1.3 mmol) was dissolved in 40 mL of toluene and 10 mL of 0.67M (CH3)2AlNH2 in benzene/toluene were added. The mixture was heated at 50° C. for 3.25 hours and water and 1N HCl added. The mixture was extracted with a large volume of ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with a gradient, 1% MeOH/methylene chloride→4% MeOH/methylene chloride, to give 450 mg (80% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.[OH:23]S(O)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Product: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Temperature: 90 °C
Yield: 82.7 %

Procedure:
To a round bottom flask was added 6-((2,4-difluorophenyl)ethynyl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (19.5 g, 65.4 mmol, Preparation #J.1) and concentrated H2SO4 (145 mL, 1630 mmol). The reaction mixture was heated to about 90° C. for about 15 min. The reaction mixture was diluted with ice water (1000 mL) and partitioned with DCM (500 mL). The aqueous layer was neutralized with 50% aqueous NaOH (about 350 mL) to about pH 7. The organic layer was isolated and the aqueous layer was extracted with DCM (3×500 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 19.5 g of crude material. The crude material was purified by silica gel chromatography using EtOAc/acetone (gradient, 1:0 to 0:1) to give title compound (17.1 g, 83%) as a brown solid. LC/MS (Table 1, Method a) Rt=2.41 min; MS m/z: 317.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:29].[K+].OO>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]([NH2:15])=[O:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(N)=O)c1ccc(F)cc1
Temperature: 65 °C
Yield: 57.9 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1; 0.5 g, 1.3 mmol) in MeOH (50 ml), was added a 25% aqueous solution (2 ml) of KOH (400 mg) at 25° C., followed by the addition of 0.1 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=30:1) to give the title compound (0.30 g, 60%). 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=7.0 Hz, 1H), 7.90 (br s, 1H), 7.35-7.32 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.00-6.95 (m, 2H), 6.00 (br s, 1H), 5.66 (br s, 2H), 5.21-5.17 (m, 1H), 1.86-1.82 (m, 1H), 1.54 (d, J=6.8 Hz, 3H), 0.96-0.92 (m, 2H), 0.69-0.67 (m, 2H). MS: Calcd.: 398. Found: [M+H]+ 399.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C([N:17]1[C:21](=[O:22])[C:20]([CH:24]([CH3:26])[CH3:25])([CH3:23])[N:19]=[C:18]1[C:27]1[N:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])(=O)C1C=CC=CC=1.[Cl-].[NH4+]>CO>[CH:24]([C:20]1([CH3:23])[C:21](=[O:22])[NH:17][C:18]([C:27]2[N:36]=[CH:35][C:34]([CH2:37][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:33][C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[N:19]1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(CBr)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reactant: Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(CSc2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of thiophenol, sodium salt and methanol is added to a solution of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(bromomethyl)nicotinic acid, methyl ester (14.08 g, 0.0298 mol) and methanol. The reaction mixture is stirred for 15 hours at room temperature, acidified with ammonium chloride (5 g, 0.0869 mol) and concentrated in vacuo to yield an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (3:1) to (1:1) as eluant to give the title compound as a yellow sold (8:32 g, 55%), mp 135°-138° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1ccnn1C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.34 g, 5.67 mmol) in Tetrahydrofuran (THF) (31 ml). 6N NaOH (31 ml, 186 mmol) was added and the reaction mixture stirred at 70° C. overnight. The reaction mixture was neutralized by slow addition of 6N HCl and partitioned between CHCl3 and H2O. The layers were separated, the organic layer dried with Na2SO4 and solvent removed. The resulting solid was used without further purification (0.71 g, 2.81 mmol, 96%): LC-MS (ES) m/z=223 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[C:5]2[N:6]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].O[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][C:27]3[CH2:44][C@:34]4([C:42]5[C:37](=[N:38][CH:39]=[CH:40][CH:41]=5)[NH:36][C:35]4=[O:43])[CH2:33][C:28]=3[CH:29]=2)[N:24]=1>CN(C=O)C>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[C:5]2[N:6]([CH2:10][C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[C:7](=[O:9])[N:8]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]5[CH2:44][C@:34]6([C:42]7[C:37](=[N:38][CH:39]=[CH:40][CH:41]=7)[NH:36][C:35]6=[O:43])[CH2:33][C:28]=5[CH:29]=4)[N:24]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)[nH]c(=O)n2CC(=O)N(C)C
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)n(Cc1ccc3cc4c(cc3n1)C[C@]1(C4)C(=O)Nc3ncccc31)c(=O)n2CC(=O)N(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-N,N-dimethylacetamide (221 mg, 0.893 mmol, described in Intermediate 17) in DMF (0.5 mL), at ambient temperature, was added sodium hydride (60% dispersion in mineral oil; 37 mg, 0.923 mmol). The resulting mixture was stirred for 30 min, then (S)-2-(chloromethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (100 mg, 0.298 mmol, described in Intermediate 11) was added and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with H2O (0.1 mL) and purified directly by silica gel chromatography, eluting with a gradient of CH2 Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2466; calculated m/z=547.2452 for C32H31N6O3.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]5[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=5)=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]5[O:32][C:31]([CH2:33][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:30][CH:29]=5)=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1

Procedure:
Prepared by an analogous method to Example 10 from 5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde and 2-methanesulphonylethylamine; δH [2H6] DMSO 9.92(1H, bs), 8.60(1H, d), 8.55(1H, s), 8.25(1H, s), 8.17(1H, s), 8.00(2H, m), 7.72(2H, m), 7.30(6H, m), 6.53 (1H, d), 5.72(2H, s) 4.55 (1H, m), 3.87 (2H, m), 3.35 (2H, m), 3.08 (3H, s), 3.04 (2H, m); m/z (M+1+) 553.