Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[OH:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>C(Cl)Cl.Cl>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([OH:33])[CH:35]=3)=[O:38])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: O=C(O)c1cccc(O)c1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O)c1cccc(O)c1

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one, 3-hydroxybenzoic acid, and WSC-HCl was stirred in CH2Cl2 at room temperature overnight. Ethyl acetate and iN HCl were added in the reaction mixture and organic layer was separated, and washed with water and brine, and dried over magnesium sulfate, evaporated in vacuo. The colorless powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(3-hydroxyphenyl)carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]1=[O:23].[OH-:24].[Na+]>O1CCOCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:23])=[O:24])=[CH:17][CH:18]=1
Reactant: Cc1ccc(CCC[C@H]2C(=O)N(OC3CCCCO3)[C@H]2C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(CCC[C@@H](C(=O)O)[C@H](C)NOC2CCCCO2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-methylphenyl)-1-propyl)-4-methylazetidin-2-one (160 mg, 0.51 mmol) in dioxane (1.5 mL) is added 1 M aqueous sodium hydroxide (0.75 mL). The solution is stirred at 23° C. for 20 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-methylphenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (114 mg, 67% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:10]([CH3:16])[C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:17])[CH:4]=[C:3]1[CH2:18][C:19]([OH:21])=[O:20].[C:22]([NH:25][CH:26](O)[CH3:27])(=[O:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:22]([NH:25][CH2:26][CH2:27][O:20][C:19](=[O:21])[CH2:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]([C:9]2[N:10]([CH3:16])[C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:17])[CH:4]=1)(=[O:24])[CH3:23]
Reactant: CSc1ccc(C(=O)c2c(C)cc(CC(=O)O)n2C)n1C
Reactant: CC(=O)NC(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2c(C)cc(CC(=O)OCCNC(C)=O)n2C)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of 1.1 g of 1,4-dimethyl-5-(1-methyl-5-methylthiopyrrol-2-oyl)pyrrole-2-acetic acid, 0.52 g of N-acetyl aminoethanol, 1.05 g DCC and 0.21 g of N,N-dimethylaminopyridine in 75 ml dry CH2Cl2 was stirred at ambient temperature for 16 hours, concentrated and extracted twice with 10 ml portions of CH2Cl2. The crude product is crystallized from ethyl acetate to yield 0.96 g (70% yield) of acetamidoethyl-1,4-dimethyl-5-(1-methyl-5-methylthiopyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C1C=CN=CC=1)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1c(F)cccc1F
Yield: 55 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (140 mg, 0.86 mmol), 2,6-difluorobenzenesulfonyl chloride (220 mg, 1.04 mmol) and DMAP (cat.) gave the title compound (160 mg, 55%) after purification by column chromatography with DCM as the eluent followed by recrystallisation with DCM/n-pentane.
Reaction SMILES: [K].[CH3:2][N:3]([CH3:34])[C:4]1[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:5]=1[CH:6]([C:15]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[CH3:34][N:3]([CH3:2])[C:4]1[CH:30]=[C:29]([N:31]([CH3:32])[CH3:33])[CH:28]=[CH:27][C:5]=1[C:6]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:15]2[C:16](=[CH:20][C:21]([N:24]([CH3:25])[CH3:26])=[CH:22][CH:23]=2)[C:17](=[O:19])[O:18]1
Reactant: COc1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1
Agent: [K]
Product: COc1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N(C)C)ccc32)cc1

Procedure:
Proceeding in a manner similar to that described in Example 1, part C above, for oxidizing the potassium salt of 2-[2,4-bis(dimethylamino)-4'-methoxybenzhydryl]-5-dimethylaminobenzoic acid, there was obtained 10.4 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(4-methoxyphenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=H; Y=4-CH3OC6H4 ; Z=2,4-[(CH3)2N]C6H3), an orange-tan-colored solid which melted at 90°-94° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[O:7][C@H:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])[O:9][C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.C(N(CC)CC)C>CCO.[Pd]>[ClH:2].[C:11]1([C@H:10]2[C:5]3[CH:4]=[CH:3][CH:27]=[CH:26][C:6]=3[O:7][C@H:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])[O:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCCNC(=O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2)O1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)CCCNC(=O)[C@H]1Oc2ccccc2[C@H](c2ccccc2)O1

Procedure:
trans-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)1,3-benzodioxan-2-carboxamide hydrochloride (1.0 g., 2.43 mmole) was mixed with triethylamine (0.526 g., 5.2 mmole) and 30% Pd on Celite catalyst (0.3 g.,) in 200 ml of absolute EtOH and hydrogenated in a Parr apparatus for 30 mins. at an initial H2 pressure of 48 psi. The uptake was 13 lbs. of H2 and after catalyst removal, the filtrate was stripped of solvent under reduced pressure. The residue was partitioned between CH2Cl2 and 2% Na2CO3 solution. After extraction of the aqueous with a second portion of CH2Cl2, the organics were combined, washed with H2O, dried (MgSO4) and stripped to a syrup under reduced pressure. The .HCL salt was formed in CH2Cl2 in the usual manner, and after solvent removal, crystallization was effected by trituration in hot EtOAc, followed by cooling (0.66 g., 72%). Recrystallization from EtOAc-abs EtOH gave analytical material (mp 165°-170° d).
Reaction SMILES: [C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH2:4]1)#[N:2].[NH3:13]>>[C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=[NH:13])[CH2:4]1)#[N:2]
Reactant: N
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Product: CC1(C)CC(=N)CC(C)(C#N)C1

Procedure:
imination of 3-cyano-3,5,5-trimethylcyclohexanone with ammonia in the presence of an imination catalyst at temperatures ranging from 20° to 150° C. and pressures ranging from 1.5 to 30 MPa to form 3-cyano-3,5,5-trimethylcyclohexanone imine followed by
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39]Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:37][O:38][CH3:39])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COCCl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
To a mixture of 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg), potassium carbonate (89 mg) and DMF (4.0 ml) was added methoxymethylchloride (39 μl) at room temperature with stirring, and the mixture was stirred at 50° C. for 12 hrs. After cooling the reaction mixture, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (75 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12]Cl)([O-:3])=[O:2].[CH3:15][C@H:16]1[O:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12][N:18]1[CH2:17][C@@H:16]([CH3:15])[O:21][C@@H:20]([CH3:22])[CH2:19]1)([O-:3])=[O:2]
Reactant: O=C(CCl)Nc1ccccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2[N+](=O)[O-])C[C@H](C)O1
Yield: 72.3 %

Procedure:
A mixture of N-(2-nitrophenyl)-2-chloroacetamide (8.6 g), 2,6-cis-dimethylmorpholine (9.2 g) and ethanol (100 ml) was heated together under reflux for 3 hours. The ethanol was evaporated off and the residue treated with water (100 ml). The resultant suspension was filtered and the solid recrystallised from ethanol to give N-(2-nitrophenyl)-2-(2,6-cis-dimethylmorpholino)acetamide (8.5 g), m.p. 127°-129° C. (with decomposition) which was then dissolved in methanol (100 ml). Platinum oxide (0.3 g) was added to the solution which was then shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature until 1.9 litres of hydrogen had been absorbed. The mixture was filtered and the ethanol evaporated off to give a white solid which was recrystallised from water to give N-(2-aminophenyl)-2-(2,6-cis-dimethylmorpholino)acetamide (5.4 g), m.p. 104°-106° C. (with decomposition).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([CH:33]=[O:34])[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1COCC1>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:33]([OH:34])[CH:30]1[CH2:31][CH2:32][N:27]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:28][CH2:29]1
Reactant: Fc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
Diisopropylamine (0.66 ml, 4.69 mmol) was dissolved in THF (30 ml) and cooled to −78° C. nBuLi (2.13 ml, 2.20 M in cyclohexane, 4.69 mmol) was added drop-wise and the reaction mixture was stirred at −78° C. for 10 min, at 0° C. for 30 min, and re-cooled to −78° C. 3-Fluoro-pyridine (0.40 ml, 4.69 mmol) was added drop-wise over 5 min, and the reaction mixture was stirred for 45 min. A solution of N-Boc-4-piperidinecarboxaldehyde (1.00 g, 4.69 mmol) in THF (10 ml) was added and the reaction mixture was warmed to RT and stirred for 15 min. The reaction mixture was quenched with sat aq NH4OAc (10 mL), diluted with EtOAc (100 mL), washed with water (2×50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil (1.42 g, 98%). LCMS (ES+): 255.0 [MH-t-Bu]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: Fc1ccc(-c2ccnc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccnc(Oc3ccc(F)c(C(F)(F)F)c3)n2)cc1
Temperature: 75 °C
Yield: 192.9 %

Procedure:
To a solution of 0.60 g (2.87 mmol) of 2B in 15 ml of dimethylformamide was added 0.46 g of K2CO3 (3.3 mmol) and 0.60 g (3.3 mmol) of 4-fluoro-3-trifluoromethyl-phenol and the resulting mixture heated at 50° C. for 15 hr and 75° C. for 24 hrs. The cooled reaction mixture was poured into a separatory funnel containing 100 mL of ethyl acetate and washed with 2×50 mL water, 3×15 mL 2.5% NaOH solution, 1×30 mL brine, dried and evaporated in vacuuo to yield 1.95 g of a mobile yellow liquid. This material was filtered through a pad of silica and re-crystallized from heptane/ethyl acetate to give 0.49 g white crystalline solid (m.p. 69-74° C.; 48%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.59 g), methyl 5-chloro-2-pyrazinecarboxylate (0.43 g) and potassium carbonate (0.69 g) were dissolved in acetonitrile (5 ml) and heated at 120° C. for 10 min in the microwave reactor, followed by a further 15 min. The crude mixture was passed through an SCX column (10 g, eluting with methanol [80 ml] then 2 N NH3 in methanol [80 ml]). The basic fractions were evaporated to give the title compound (E1) as a yellow solid (0.665 g). MS electrospray (+ion) 373 (MH+)
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[NH2:23][C:24]1[N:29]=[C:28]2[NH:30][CH:31]=[C:32]([CH:33]=[C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:35]([NH2:37])=[O:36])[C:27]2=[CH:26][CH:25]=1>ClCCl>[C:1]1([CH2:7][C:8]([NH:23][C:24]2[N:29]=[C:28]3[NH:30][CH:31]=[C:32]([CH:33]=[C:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:35]([NH2:37])=[O:36])[C:27]3=[CH:26][CH:25]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=O)C(=Cc1c[nH]c2nc(N)ccc12)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C(=Cc1c[nH]c2nc(NC(=O)Cc3ccccc3)ccc12)c1ccccc1
Yield: 64.7 %

Procedure:
500 mg (3.67 mmol) of phenylacetic acid were dissolved in 20 ml of dichloromethane and 705 mg (3.67 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added at 0° C. The mixture is maintained at the same temperature for 30 minutes and then a solution of 680 mg (2.44 mmol) of 3-(6-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-propenamide in 10 ml of dichloromethane was added dropwise. After 6 hours at room temperature the mixture was washed with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column by using a mixture cyclohexane/ethylacetate 4/1 to give 626 mg (65% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C([BH3-])#N.[Na+].[C:49]1(=O)[CH2:52][CH2:51][CH2:50]1.C([O-])(O)=O.[Na+]>CO.CC(O)=O>[CH:49]1([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:52][CH2:51][CH2:50]1
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Reactant: O=C1CCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C2CCC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.84 g, 1.4 mmol) was taken up in methanol (10 ml) and Sodium cyanoborohydride (0.087 g, 1.4 mmol) was added. The pH was adjusted to ca. 6 using a 10% solution of AcOH in MeOH, then Cyclobutanone (0.15 ml, 2.1 mmol) added in one portion. The reaction was stirred at RT for 3 days. NaHCO3 (sat'd) added to the reaction mixture which was then extracted (3×) with DCM. The combined organics were dried with MgSO4, filtered and concentrated. The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>C(OCC)C>[CH2:4]([NH:5][C:12]([NH:11][CH2:10][CH2:9][Cl:8])=[O:13])[CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: O=C=NCCCl
Reactant: CC(C)(C)CCN
Solvent: CCOCC
Product: CC(C)(C)CCNC(=O)NCCCl
Reaction time: 2 h

Procedure:
A 5 g quantity of 3,3-dimethyl butylamine (0.5 mol) was dissolved in 30 ml of anhydrous diethyl ether and stirred on an ice bath. 2-Chloroethyl isocyanate (5.25 g, 0.5 mol) dissolved in 15 ml of ether was added maintaining a temperature of 10° C. or less, and stirring continued for 2 hrs. Filtering the product and washing with four 5 ml portions of chilled ether afforded 6.2 g (60%) which melted at 84° C. (decomposes). IR analysis showed peaks at 1625/cm (C=O) and 1580/cm (N--C=O). NMR: singlet (9H) at 0.9 ppm, multiplet (2H) at 1.3 ppm, multiplet (2H) at 3.2 ppm, multiplet (4H) at 3.5 ppm, singlet (1H) at 5.5 ppm, and singlet (1H) at 5.7 ppm.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: Nc1ccc(CCO)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(CCO)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminophenethyl alcohol as the aniline component. (41%, MS=500.2 (M+H))
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=2)[N:3]=1.[NH2:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1>>[CH2:8]([C:6]1[N:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=2)[N:3]=[C:2]([NH:26][C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=2)[CH:7]=1)[CH3:9]
Reactant: Cc1cc(N)n[nH]1
Reactant: CCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: CCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-ethyl-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 32) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:31][CH:28]([CH3:30])[CH3:29])=[C:14]([O:23][CH3:24])[CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27]
Reactant: CC(C)N
Reactant: COc1ccc2cc(-c3ccc(OCC4CO4)c(OC)c3)n(C)c(=O)c2c1
Product: COc1ccc2cc(-c3ccc(OCC(O)CNC(C)C)c(OC)c3)n(C)c(=O)c2c1
Yield: 77 %

Procedure:
2-Methyl-3-[3-methoxy-4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[3-methoxy-4-(2,3-epoxypropoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine.
Reaction SMILES: [N:1]([C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N+]=[N-]>ClC1C=CC=CC=1Cl.CCCCCC>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20]([C:5]3[CH:6]=[C:7]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[CH:8]=[C:9]([C:10]#[N:11])[C:4]=3[NH:1]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2cc(C#N)c(N=[N+]=[N-])c(-c3ccc(OC)cc3)c2)cc1
Solvent: Clc1ccccc1Cl
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C#N)c3[nH]c4cc(OC)ccc4c3c2)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 4′-azido-4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-carbonitrile (108 mg, 0.303 mmol) in 1,2-dichlorobenzene (2 mL) was heated at 180° C. for 0.5 hr. It was allowed to cool to room temperature and diluted with hexane (about 5 mL). The precipitate was collected by filtration and washed with hexane to leave 7-methoxy-3-(4-methoxyphenyl)-9H-carbazole-1-carbonitrile (72 mg, 72% yield) as an off-white solid. MS (ESI) m/z 329.1 (M+H). 1H NMR (CDCl3) δ ppm 8.51 (1H, s), 8.28 (1H, s), 7.96 (1H, d, J=8.85 Hz), 7.76 (1H, d, J=1.83 Hz), 7.53-7.59 (2H, m), 7.00-7.04 (2H, m), 6.99 (1H, d, J=2.14 Hz), 6.93 (1H, dd, J=8.70, 2.29 Hz), 3.92 (3H, s), 3.87 (3H, s).