Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[OH:15]O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[N+:5]([O-:15])[CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: CCOc1nc(N)nc2nccnc12
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(N)nc2c1ncc[n+]2[O-]
Reaction time: 48 h
Yield: 32 %

Procedure:
To a cooled (0° C.) solution of the compound of example 7 (2.47 g, 12.9 mmoles) in trifluoroacetic acid (53 ml) was added dropwise 2.53 ml of a 35% aqueous H2O2 solution. The reaction mixture was kept at 4° C. for two days in the refrigerator, whereby another 1.25 ml of the same H2O2 solution was added after 1 day. The solution was concentrated in vacuo. The residue was suspended in water and neutralized by the addition of a concentrated ammonia solution. Evaporation of the solvent in vacuo and purification of the residue by flash chromatography (silica, using a CH3OH/CH2Cl2 mixture (6:94) as the eluent) provided the title compound as a yellow powder (861 mg, yield: 32%). Mass spectrum data are as follows: m/z (%): 230 ([M+Na]+, 30), 208 ([M+H]+, 100), 180 [(M+H-ethene)+, 10].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].Cl.N>O1CCOCC1.CO>[NH3:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2)=[O:23]
Reactant: CN(CCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CNCCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 112 %

Procedure:
[3-[[4-Chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]propyl]methyl-carbamic acid, 1,1-dimethylethyl ester (0.236 g, Example 23b), 4 M hydrogen chloride in 1,4-dioxane (5 ml) and methanol (5 ml) were stirred together under nitrogen for 3 h, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica gel, eluting with 19:1:0.1/dichloromethane:methanol:ammonia to afford the title compound as an oil (0.106 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:19](=[O:20])[CH2:18][CH2:17][O:16][CH3:15])=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Reactant: COCCC(=O)Cl
Solvent: CCOCC
Product: COCCC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 2.62 g. of 1-(2',4'-difluoro-4-biphenylyl)-3-hydroxypropan-1-one, obtained by acylating 2,4-difluorobiphenyl with 3-methoxypropionyl chloride to give 1-(2',4'-difluoro-4-biphenylyl)-3-methoxypropan-1-one and subsequently effecting ether scission, in 20 ml. of THF is added dropwise, at 20° to stirred Grignard solution prepared from 3 g. of methyl iodide and 0.5 g. of magnesium in 100 ml. of ether. The mixture is stirred for 4 hours more and the resulting alcoholate is decomposed with water and dilute sulfuric acid. The reaction mixture is worked up in the custromary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: CC([N:5]([C@@H:9]([C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:21][CH:22]=1)=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:11][C:10]([CH3:13])([CH3:12])[C@H:9]([C:14]([NH:16][C:17]1[CH:18]=[N:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:21][CH:22]=1)=[O:15])[NH2:5]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](N(C(=O)[O-])C(C)(C)C)C(C)(C)C)cn2)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)(C)C)cn2)ccc1C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-2,2-dimethyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 96, 8.2 mg) in dry dichloromethane (0.5 mL) cooled to 0° C., TFA (57 μl, 0.740 mmol) was added dropwise and the solution was stirred for 3 hours at that temperature. The volatiles were evaporated. The residue was dissolved with dichloromethane (2 mL) and an aqueous saturated solution of NaHCO3 was added (4 mL). The layers were separated and the aqueous layer was extracted twice with dichloromethane. The gathered organic layers were dried over sodium sulphate and evaporated to afford the title compound (6.2 mg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH:11]=O.[NH2:13]/[C:14](/[CH3:21])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:21][C:14]1[NH:13][C:14]([CH3:21])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1sc2ccccc2c1C=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1c(C)sc2ccccc12
Yield: 43.1 %

Procedure:
A mixture of 2.2 g of 2-methylbenzo[b]thiophene-3-carboxaldehyde, 4.9 g of ethyl 3-aminocrotonate, and 10 ml of ethanol were heated to reflux for approximately 18 hours. An additional 1.6 g of ethyl 3-aminocrotonate were added and the reaction was heated an additional 24 hours at reflux. The reaction mixture was cooled and concentrated and the resulting solid was recovered by filtration providing 2.15 g of the desired title product, m.p. 191°-193° C.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:11])=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCCl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(N(C)c2ccc(O)cc2)c2ccccc2n1
Temperature: 10 °C

Procedure:
To a solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine hydrochloride salt (106 mg, 0.336 mmol) in dichloromethane (10 mL) at −78° C. was added slowly boron tribromide (1M in CH2Cl2, 0.75 mL) under argon. The cold bath was removed and the reaction mixture was allowed to warm up slowly to 10° C. in 1. 5 h. The reaction mixture was quenched with water (10 mL), basified with 2N NaOH to pH=10, and extracted with EtOAc (2×25 mL). The EtOAc extracts were dried and evaporated to give a light brown residue. The crude was purified by column chromatography (SiO2, EtOAc:hexanes/15-50%) to give the product as a white solid, which was further purified by recrystallization from MeOH: 1H NMR (acetone-d6) 8.74 (s, 1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.20-7.18 (m, 3H), 7.12 (m, 1H), 7.04-6.99 (m, 2H), 3.64 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: C[C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH3:14])[C:5]([C:11]([OH:13])=[O:12])=[N:6][C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+]>O.CO>[CH3:14][C:4]1[C:5]([C:11]([OH:13])=[O:12])=[N:6][C:7]([C:8]([OH:10])=[O:9])=[CH:2][C:3]=1[O:15][CH3:16]
Reactant: COc1c(C)c(C(=O)O)nc(C(=O)O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)nc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
3.0 g of dimethyl 4-methoxy-pyridin-2,6-dicarboxylic acid (compound F6) are dissolved in 280 ml of water and 420 ml of methanol. After cooling to 0° C., 14.65 ml of a sodium hydroxide solution (strength 1.0 M) is added dropwise (15 min). After 1 h, the mixture is allowed to warm up to room temperature and is stirred for further 21 h during which time 2.0 ml of sodium hydroxide solution are gradually added. Subsequently, 6.5 g of acidic ion exchange resin (Amberlite IR-120 [H+]) are added for neutralization. Thereafter, the mixture is filtered and the filtrate is concentrated in vacuum to yield 2.8 g of the title compound as a colorless oil. TSP-MS: 212.1 [MH+]. TLC: Rf=0.1-0.2 (dichlormethane/methanol 5:1, 3.0 vol.-% acetic acid).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH2:10]([O:9][C:2](=[O:8])[C:3](=[O:5])[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[O:18])[CH3:11]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCCCC1=O
Temperature: 60 °C

Procedure:
A solution of sodium (1.75 g) in ethanol (100 ml) was treated with a mixture of diethyl oxalate (9.41 ml) and cyclohexanone (7.18 ml). The mixture was heated to 60° C. for 5 hours then cooled and then evaporated to yield oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester as a brown foam (16.635 g). LC-MS (METHOD B): RT=3.10 minutes; 197 (M−H)−. (b) 5-Methyl-2,4-dioxo-hexanoic acid ethyl ester
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:17]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a stirring solution of 3-aminobenzoic acid (1.1 g, 7.9 mmol) in anhydrous THF (20 mL), 3-(trifluoromethyl)benzoyl chloride (2.0 g, 9.6 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from chloroform to afford the title compound as a white solid (1.2 g, 49%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([Cl:19])=[N:14]3)[C:4]1=[O:20].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:19][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:33]([C:29]3[CH:28]=[CH:27][C:26]4[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH:30]=3)(=[O:35])=[O:34])[C:4]2=[O:20])[N:14]=1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N[C@H]1CCN(Cc2cccc3nc(Cl)ccc23)C1=O
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc5nc(Cl)ccc45)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 5-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride in place of 7-(3-(S)-amino-2oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is purified by column chromatography eluting with 25% EtOAc/CH2Cl2 to provide the title compound as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>C(O)CC.ClCCl>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: ClCCl
Solvent: CCCO
Product: Cc1ccc(-c2cn3cc([N+](=O)[O-])ccc3n2)cc1
Yield: 22.9 %

Procedure:
S1 g (0.38 mole) of 1-bromo-2-(4-methylphenyl)-2-ethanone and 53 g (0.3S mole) of 2-amino-5-nitropyridine are reacted in 900 ml of n-propanol. The solution is maintained under reflux, the reaction being followed by thin layer chromatography. When there is no further change, the mixture is evaporated to dryness. The residue is taken up with water and treated with ammonia solution 1 10 until the pH >8. The insoluble material is filtered off and dried, and then treated with dichloromethane. The insoluble portion is recrystallized in ethyl acetate, which yields a first crop. The mother liquors are then combined with the portion soluble in dichloromethane, the mixture is concentrated and a second crop of product is obtained. The two crops are purified separately by chromatography. 22 g (23%) of yellow solid are obtained overall.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C#N)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[C:20](=[O:23])([O-])[O-:21].[Na+].[Na+].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:20]([OH:21])=[O:23])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 4 h

Procedure:
To a flask containing 2-(4-bromo-3-(trifluoromethyl)phenyl)acetonitrile 46-5 (880 mg, 3.3 mmol) were added water (4.5 mL) and dropwise concentrated sulfuric acid (4.5 mL). The reaction mixture was stirred at 115° C. for 4 hours. After cooled down to room temperature, the reaction mixture was poured into water (100 mL). The resulting solution was neutralized with powder sodium carbonate to pH 12, treated with 1N HCl aqueous solution to pH around 2, and extracted with dichloromethane (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and then taken to dryness by rotary evaporation give 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 as pale yellow solid. MS m/z 283.1 (M+1)
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)[N:37]1[CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45].NN>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:37][CH2:42][CH2:43][S:44]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:46])=[O:45]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=C1CCC(=O)N1CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol) in DMF (3 mL) was added diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 2-(2,5-dioxo-1-pyrrolidinyl)ethanesulfonyl chloride (53 mg, 0.168 mmol). After the reaction mixture was stirred at room temperature overnight, hydrazine (4 eq) was added. The reaction mixture was stirred for 4 hrs. The solution was filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (10 mg, 17%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24]([O:26]C)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cc(C)cc(C)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (200 mg, 0.55 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 4 days at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 2.5 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (47%) of the 9-[(3,5-dimethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.75 (d, 1H, J=8 Hz), 7.45 (m, 2H), 7.3 (t, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.85 (s, 1H), 6.7 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 2.2 (s, 6H). IR (KBr, cm−1) 3417, 3198, 3113, 3063, 1631, 1601, 1562, 1438, 1332, 1263, 1217, 781, and 773. MS (ES) m/e 343, 345.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][NH2:11].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:11][CH3:10])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1ccc(Cl)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CN=Cc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
In 30 ml of toluene, 0.8 g (5.7×10-3 moles) of 6-chloropyridine-3-aldehyde and 10 g of Na2S4 were mixed and while the mixtures was stirred, a 40% aqueous solution of methylamine (1.4 g, 1.1×10-2 mole) was added dropwise over 30 minutes, followed by addition of 10 g of MgSO4. The mixture was allowed to stand at room temperature overnight, after which it was filtered. The filtrate was concentrated to give 0.6 g (yield 68%) of N-(6-chloro-3-pyridylmethylidene)methylamine as crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[CH3:19][C:20]1(C)[C:24](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(COC)OC>[N+:16]([C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:2]([C:20]([CH3:24])=[CH2:19])=[N:3][CH:4]=1)([O-:18])=[O:17]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1cc(NCc2ccccn2)c([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitro-N-(pyridin-2-ylmethyl)pyridin-4-amine E-2.17″ (125 mg; 0.47 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (200 μl; 1.06 mmol), cesium carbonate (300 mg; 0.90 mmol) and [1,1′-Bis[diphenylphosphino]-ferrocene]dichloropalladium (30 mg; 0.04 mmol) are suspended in 7.5 ml dimethoxyethane and 2.5 ml water and heated for 1 h at 100° C. The solvent of the reaction mixture is removed under reduced pressure and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([F:24])[CH:8]=1)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C1CCCCC1>ClCCl>[F:24][C:9]1[CH:8]=[C:7]([CH:5]([O:49][CH2:48][C:35]2([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (±)-1-(5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-yl)ethyl 2,2,2-trichloroacetimidate (1.121 g, 2.465 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.839 g, 2.71 mmol) in dichloromethane (6 mL) at 0° C. was added cyclohexane (5.61 mL) and tetrafluoroboric acid diethyl ether complex (0.017 mL, 0.123 mmol). The reaction was stirred at 0° C. for 10 min. The reaction was treated with an additional portion of tetrafluoroboric acid diethyl ether complex (9 μL, 0.065 mmol) and stirred at 0° C. for 30 min. The reaction was quenched by addition of saturated sodium bicarbonate, diluted with diethyl ether, and poured into water. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→22% EtOAc/Hex) gave 922 mg (62.2%) as an amorphous foam solid. 1H-NMR (CDCl3, 300 MHz) δ 7.98 (s, 1H), 7.26-7.32 (m, 2H), 6.97-7.08 (m, 3H), 6.64-6.68(m, 1H), 5.62 (s, 2H), 4.92 (q, J=6.0 Hz, 1H), 3.65-3.75 (m, 2H), 3.58 (m, 2H), 3.35 (m, 2H), 2.9-3.1 (m, 2H), 1.8-2.2 (m, 4H), 1.39-1.42(m, 12H), 0.88(m, 2H), −0.07 (s, 9H); Mass spec.: 602.54 (MH)+.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:28]=[C:27]2[CH2:38][NH:39][CH:40]1[CH2:42][CH2:41]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][O:53][C@@H:52]([C:56](O)=[O:57])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:28]=[C:27]2[CH2:38][N:39]([CH:40]1[CH2:42][CH2:41]1)[C:56]([C@@H:52]1[O:53][CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:51]1)=[O:57]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COCCCn1cc(CNC2CC2)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCn1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole (162 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg) were added successively to a solution of N-{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}cyclopropanamine (a compound of Reference Example 127(2), 405 mg) and (2R)-4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid (231 mg) in N,N-dimethylformamide (12.5 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate and saturated brine successively and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=50/50 to 10/90) to give tert-butyl(2R)-2-{[{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (581 mg) as a colorless oil.
Reaction SMILES: C([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:12][C:13]=2[NH2:17])C1C=CC=CC=1.C(O)(C)C.[H][H]>[OH-].[OH-].[Pd+2].C(O)=O>[CH3:23][O:22][C:20]([CH2:19][CH2:18][C:11]1[N:10]=[C:9]2[C:14]([NH:15][CH:16]=[N:8]2)=[C:13]([NH2:17])[N:12]=1)=[O:21]
Reactant: COC(=O)CCc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=CO
Product: COC(=O)CCc1nc(N)c2[nH]cnc2n1
Yield: 92.5 %

Procedure:
9-Benzyl-2-(2-methoxycarbonylethyl)adenine (0.29 g, 0.93 mmol) obtained by Example 61 and 20% Pd(OH)2/C (0.32 g) were added to a mixed solvent of isopropanol (8 ml) and formic acid (8 ml), and the mixture was stirred at a pressure of 2 atmosphere of hydrogen at 70° C. for 40 hours. After filtration, the filtrate was concentrated to give the captioned compound (0.23 g, 0.86 mmol) as a white solid.