Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.Cl.[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1>C1COCC1>[OH:38][CH:36]1[CH2:37][N:34]([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:35]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.5 g, 2.76 mmol), CDI (0.671 g, 4.14 mmol), the mixture was stirred for 2 hrs at 0° C. followed by addition of triethylamine (1.2154 ml, 8.28 mmol) and azetidin-3-ol hydrochloride (0.756 g, 6.90 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford the title product (0.51 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:17]([C:21]1[NH:25][C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=1)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=[C:21]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
Intermediate (2a) (13.6 g, 45 mmol, 1.0 eq), 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (8.4 g, 45 mmol, 1.0 eq) and potassium carbonate (12.4 g, 90 mmol, 2.0 eq) were added to 90 mL of DMF. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 300 mL EtOAc and extracted with 100 mL 10% aq. LiCl, 2×200 mL water, 100 mL saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was evaporated and purified by flash chromatography (40% EtOAc:hexanes) to yield intermediate (2b) (13.0 g). MS m/z: [M+H+] calcd for C19H26ClN3O3S, 412.1; found 412.4.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.C1(C)C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Temperature: 140 °C

Procedure:
2-Chloro-5-(trifluoromethyl)aniline (2) (200 g, 1.023 mol), diethyl 2-(ethoxymethylene)malonate (3) (276 g, 1.3 mol) and toluene (100 mL) were combined under a nitrogen atmosphere in a 3-neck, 1-L round bottom flask equipped with Dean-Stark condenser. The solution was heated with stirring to 140° C. and the temperature was maintained for 4 hours (h). The reaction mixture was cooled to 70° C. and hexane (600 mL) was slowly added. The resulting slurry was stirred and allowed to warm to room temperature. The solid was collected by filtration, washed with 10% ethyl acetate in hexane (2×400 mL) and then dried under vacuum to provide the product, diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino)methylene)malonate (4), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (d, J=13.0 Hz, 1H), 8.63 (d, J=13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.50 (dd, J=1.5, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.17 (q, J=7.1 Hz,2 H), 1.27 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Br)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@H:9]1[CH:10]([OH:11])[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([CH2:24][OH:23])=[CH:26][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: OCc1ccc(Br)c2ccccc12
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccc(CO)c2ccccc12
Yield: 43.8 %

Procedure:
(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-[hydroxy(4-hydroxymethyl-1-naphthyl)methyl]pyrrolidine (2.71 g, yield: 44.0%) was prepared as a colorless oily substance from (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (4.17 g, 12.7 mmol), 4-hydroxymethyl-1-bromonaphthalene (3 g, 12.7 mmol) and 1.6M n-butyl lithium-hexane solution (20.6 ml, 39.9 mmol), in the same manner as in Reference Example 111-1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH:19]([CH3:21])[CH3:20])[C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:18]1[C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH:19]([CH3:21])[CH3:20])[CH:17]=1
Reactant: CC(C)n1ccc2c(Cl)ncnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)n1cc(Br)c2c(Cl)ncnc21
Yield: 93.4 %

Procedure:
N-Bromosuccinimide (165 g, 926 mmol) was added to a solution of 4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (151 g, 772 mmol) in CH2Cl2 (1 L). After 12 h the reaction was quenched with saturated aqueous NaHCO3 (500 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×500 mL). The combined organic layers were washed with water (3×500 mL) and brine (1×500 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound as a white solid (198 g, 94%). MS: 275.5 (MH+); HPLC Rf: 5.99 min. (HPLC method 4).
Reaction SMILES: O(CCCCCCC=O)C1C=CC=CC=1.C([O:18][C:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=[O:18])=[CH:32][CH:31]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)CCCCCCOc1ccc(OCc2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=CCCCCCCOc1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Product: O=CCCCCCCOc1ccc(OCc2ccccc2)cc1
Yield: 62.4 %

Procedure:
7-[4-(Benzyloxy)phenoxy]heptanal 62.2 was synthesized analogous to the preparation of 62.1 using 61.2/20.4 (0.624 g, 2 mmol) and diisobutylaluminum hydride (4.5 mL, 4.5 mmol, using a 1M solution in hexanes) in THF (20 mL). Purification by flash column chromatography on silica gel gave 62.2 (0.39 g, 63% yield) as a white solid (m p 65-67° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][C:20]3=[O:25])=[CH:12][CH:11]=[CH:10][N:9]2[CH:26]=1)=[O:5])[CH3:2].[CH:27](=O)[CH2:28][CH2:29][CH3:30].N1CCCCC1>C(O)C>[CH:27](=[C:22]1[S:21][C:20](=[O:25])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[C:8]3[N:9]([CH:26]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=3)[CH:10]=[CH:11][CH:12]=2)[C:23]1=[O:24])[CH2:28][CH2:29][CH3:30]
Reactant: CCCC=O
Reactant: CCOC(=O)c1cn2cccc(OCCCCN3C(=O)CSC3=O)c2n1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(C(=O)OCC)nc23)C1=O

Procedure:
To a solution of 1.88 g (5.0 mmol) of 3-[4-(2-ethoxycarbonylimidazo[1,2-a]pyridin-8-yloxy)butyl]-thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/2) to yield 2.14 g (99.2%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][CH2:23][OH:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][CH:23]=[O:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(CCO)ccc3c2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CC=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of 2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-ethanol (170 mg, 0.52 mmol) in methylene chloride (5 mL) was added Dess-Martin periodinane (0.31 g, 0.73 mmol). After stirred at room temperature for 1 hour, the solution was diluted with methylene chloride, washed with sodium thiosulfate aqueous, dried over Na2SO4, and concentrated. The crude was purified via silica gel column to afford white solid (120 mg, yield: 70%). ESI-MS: 325.20 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][CH:14]1[NH:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:19]1[CH2:18][CH2:17][NH:16][C:15](=[O:20])[CH:14]1[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC1NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1C(=O)NCCN1c1nncc2cc(Br)ccc12
Temperature: 190 °C
Yield: 60.5 %

Procedure:
In three separate sealed tubes were placed a mixture of 6-bromo-1-chlorophthalazine (0.250 g, 1.03 mmol), 3-methylpiperazin-2-one (0.239 g, 2.09 mmol), K2CO3 (0.155 g, 1.12 mmol) and 5 mL of CH3CN. The three reactions were heated at 190° C. for 15 min in a microwave oven. The reaction mixtures were combined, concentrated onto silica gel and purified using flash chromatography eluting with 2M NH3 in MeOH/CH2Cl2 (0:1→1:19) to give 200 mg (60%) of an orange oil.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH2:7])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([C:14](=O)[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[CH:12][CH:11]=1.O.Cl>C(O)(=O)C>[ClH:9].[CH:1]([NH:4][CH:5]([CH3:8])[CH2:6][N:7]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[CH:15]=[C:14]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:25][CH:24]=1)([CH3:3])[CH3:2]
Reactant: O=C(CC1CCCCC1=O)c1ccc(Cl)cc1
Reactant: CC(C)NC(C)CN
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)NC(C)Cn1c(-c2ccc(Cl)cc2)cc2c1CCCC2

Procedure:
5.8 g (0.05 mole) of 2-isopropylaminopropylamine are added dropwise to a stirred solution of 12.5 g (0.05 mole) of 2-(p-chloro-phenacyl)cyclohexanone [Example 20(a)] in glacial acetic acid dropwise under nitrogen. After refluxing for 5 hours, the reaction mixture is cooled and poured into 500 ml. of water. The pH is adjusted to 1 with dilute hydrochloric acid, at which point a tan solid separates. This solid is recrystallized from methanol and then twice from an isopropanol-ether mixture to give 1-(2-isopropylaminopropyl)-2-(p-chlorophenyl)-4,5,6,7-tetrahydroindole hydrochloride as tan crystals, m.p. 192°-194° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:34](OC[C@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)O)(=O)C(C)(C)C>>[C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:34])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Cl)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1

Procedure:
Compound 2I was prepared following the procedure used to prepare compound 1J of Example 1, except that (S)-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate (2H) was used instead of compound 1I. LCMS-ESI+ (m/z): 468.3, 470.3 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]4=[O:37])=[N:28][CH:29]=3)=[CH:21][N:20]=[CH:19]2)[CH:14]=[CH:13][C:12]=1[C:38]#[N:39])(C)(C)C>CO>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]4=[O:37])=[N:28][CH:29]=3)=[CH:21][N:20]=[CH:19]2)[CH:14]=[CH:13][C:12]=1[C:38]#[N:39]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Temperature: 0 °C

Procedure:
(2-{5-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-2-cyano-phenoxy}-ethyl)-carbamic acid tert-butyl ester from step 4 (260 mg, 0.46 mmol) was dissolved in MeOH (15 ml) and cooled to 0° C. HCl(g) was then bubbled into the solution until saturated. The reaction mixture was allowed to warm up to room temperature. The solvent was removed in vacuo to yield the final product.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[NH:19][C:20]=1[Br:21]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:22]([C:18]2[NH:19][C:20]([Br:21])=[C:16]([Br:15])[CH:17]=2)=[O:23])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc(Br)c(Br)[nH]2)C1

Procedure:
60.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4,5-dibromo-1H-pyrrole-2-carboxylic acid to give (R)-3-{[(4,5-dibromo-1H-pyrrole-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS449.9 ([M−H]−)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH3:28])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:29]2[CH2:31][CH2:30]2)[C:7]=1[S:32](C)(=O)=O)=[O:5])[CH3:2].O.[SH-].[Na+]>COCCOC.O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH3:28])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:29]2[CH2:30][CH2:31]2)[C:7]=1[SH:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O

Procedure:
Compound 7 (1.04 g, 2.04 mmol) is partially dissolved in DME (40 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate (Aldrich, 72.6% by titration, 465 mg, 6.02 mmol) in water (3.0 mL) is added to this solution. The resulting mixture is sparged slowly with argon for 30 min. The progress of the reaction is monitored by HPLC-MS, and judged to be complete (≦2% of 7 remains) after 11.5 h. Excess sodium hydrosulfide is quenched upon addition of aq HCl (4.5 mL, 4 N). The resulting orange solution (pH ˜2) is sparged with argon (30 min) to remove the generated hydrogen sulfide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][O:10][C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=4[NH:16][C:15]=3[N:14]=[CH:13][CH:12]=2)([CH3:8])[CH2:4][CH2:3]1.[Cl:26]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:26][C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:17]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[C:19]=2[C:11]=1[O:10][CH2:9][C:5]1([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Solvent: CC(C)O
Solvent: CC#N
Product: CN1CCC(C)(COc2c(Cl)cnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of 4-((1,4-dimethylpiperidin-4-yl)methoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.16 mmol), N-chlorosuccinimide (60 mg, 0.45 mmol) in acetonitrile (0.8 mL) and isopropyl alcohol (0.23 mL) was stirred at 40° C. for 16 hours. The reaction mixture was diluted acetonitrile (1 mL) and the solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (12 mg, 20%). 1H NMR (500 MHz, d6-DMSO) δ 9.04 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 4.28 (s, 2H), 2.51-2.46 (m, 2H), 2.28 (m, 2H), 2.22 (s, 3H), 1.82 (m, 2H), 1.51 (m, 2H), 1.19 (s, 3H), NH signal not observed. LCMS (Method D): RT=8.445 min, M+H+=370.1.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46]
Reactant: CN(C)CCCO
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 3-dimethylamino propanol (31.6 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 133 as an off-white solid in 25.4% yield. LCMS m/z (%)=464 (M+H 35Cl, 100), 466 (M+H 37Cl, 39). 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.47 (s, 1H), 8.07-8.01 (m, 1H), 7.62 (s, 1H), 7.51 (d, J=8.90 Hz, 1H), 7.38 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (d, J=9.02 Hz, 1H), 7.03-6.97 (m, 1H), 4.11-3.94 (m, 2H), 3.63 (s, 3H), 2.28-2.18 (m, 2H), 2.11 (s, 6H), 1.78-1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5](F)[C:6]2[C:10]=1[N:9]=[CH:8][C:7]=2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:18]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:26]1[CH2:31][CH2:30][N:29]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]=3)[NH:9][CH:8]=2)=[O:15])[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C([O-])C(=O)c1cnc2c(Cl)ccn(F)c1-2
Agent: [K+]
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12

Procedure:
Precursor 5p, 1-benzoyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-chloro-4-fluoro-4-azaindol-3-yl)oxoacetate, Precursor 4e, and 1-benzoyl-piperazine. 1H NMR (500 MHz, CD3OD) δ8.83 (s, 1H), 8.63 (d, 1H, J=5.35 Hz), 7.91 (d, 1H, J=5.75 Hz), 7.47 (m, 5H), 3.80-3.30 (m, 3H). MS m/z: (M+H)+ Calc'd for C20H18ClN4O3: 397.11; Found 397.02. HPLC retention time: 1.20 minutes (column A).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26](Cl)[C:21]3=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([CH3:29])[C:21]3=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Product: Cc1nccn2c1cnc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of benzyl((trans)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (6.58 g, 16.50 mmol) and potassium carbonate (3.42 g, 24.74 mmol) in 1,4-dioxan (200 ml) was added (after flushing with nitrogen) trimethylboroxine (13.84 ml, 49.5 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (1.217 g, 1.650 mmol). The reaction was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered over Celite and Celite washed with ethyl acetate. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate with gradient of 0 to 10% of methanol) to yield benzyl((trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (3.52 g)
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)#[N:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: N#Cc1ccccc1C=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1C=NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 2-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (22.2 mg, yield: 94%).
Reaction SMILES: [CH3:1][C:2]1([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[CH:4]1[CH2:12][CH:7]2[CH:6]=[CH:5]1>CO.[Pd]>[CH3:1][C:2]1([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[CH:4]1[CH2:12][CH:7]2[CH2:6][CH2:5]1
Reactant: CC1(O)CCCC2C3C=CC(C3)C21
Agent: [Pd]
Solvent: CO
Product: CC1(O)CCCC2C3CCC(C3)C21

Procedure:
25 g (0.140 mole) of 3-methyl-tricyclo[6.2.1.02,7 ]undec-9-en-3-ol--see Example 1--in 150 ml of methanol were hydrogenated under atmospheric pressure and at room temperature in the presence of 2.5 g of 10% palladium on charcoal. After filtration, evaporation and distillation (b.p. 60°-65°/0.1 Torr), 24 g of a material containing ca. 90% of the desired compound according to vapor phase chromatographic analysis were isolated.