Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O)[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[K].[CH:27]([CH2:29][CH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]1)=O.O>COCCOC>[CH2:30]([C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]1)[CH2:29]/[CH:27]=[CH:1]/[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC=O)CC1
Reactant: CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: COCCOC
Solvent: O
Product: C/C=C/CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 5-ethylsulfonyl-1-phenyl-1H-tetrazole (5.0 g) and anhydrous ethylene glycol dimethyl ether (50 ml) at −60° C. was added 0.5 M potassium hexamethyldisilazane solution (in toluene, 19.7 ml), and the mixture was stirred for 20 minutes. Under the same condition, a solution of t-butyl trans-4-(2-formylethyl)cyclohexylcarbamate (2.65 g) (Example 73 (3)) in anhydrous ethylene glycol dimethyl ether (20 ml) was added thereto. The reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added water, and the mixture was stirred for 1 hour, then extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 252 mg of t-butyl trans-4-[(E)-3-pentenyl]cyclohexylcarbamate.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC([C:11]3[CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=[N:15][CH:16]=3)=CC=2N=1.C[N:27](C)CCN>>[N:15]1[CH:16]=[CH:11][CH:12]=[C:13]([C:17]([NH2:27])=[O:19])[CH:14]=1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN(C)CCN
Product: NC(=O)c1cccnc1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with N,N-dimethylethylenediamine via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)pyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)pyridine-3-carboxamide (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 22.3 mg of 343. MS (Q1) 529.0 (M)+
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.[Pd].O>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[C:19](/[CH:21]=[CH:22]/[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C(=C/c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)\c1cccnc1
Temperature: 100 °C
Yield: 22.2 %

Procedure:
A stirred mixture of (R)-indan-1-yl-(6-vinyl-4H-benzo[d][1,3]oxazin-2-yl)-amine (Example 134) (250 mg, 0.86 mmol), 3-bromopyridine (177 mg, 1.12 mmol), tri(o-tolyl)phosphine (21 mg, 0.07 mmol), triethylamine (261 mg, 2.58 mmol) and palladium actetate (7.73 mg, 0.034 mmol) in N,N-dimethylformamide (3 ml) was heated in a sealed tube at 100° C. for 3 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with water (2×20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) yielded the title compound as yellow solid (70 mg, 22%). MS (ISP): m/e=368.2 (M+H+); m.p. 132° C.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]1>>[Cl:14][C:4]1[CH:3]=[C:2]([CH:21]([C:19]2[N:18]=[CH:17][N:16]([CH3:15])[CH:20]=2)[OH:22])[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1
Reactant: Cn1cnc(C=O)c1
Reactant: CC1(C)OCc2cc(Cl)cc(Br)c2O1
Product: Cn1cnc(C(O)c2cc(Cl)cc3c2OC(C)(C)OC3)c1
Yield: 63.5 %

Procedure:
Starting from 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin and 1-methyl-1H-imidazole-4-carboxaldehyde. The addition of the organomagnesium compound is carried out at 0° C. Yield: 63.5% of theory; M.P.: 131°-136° C. (recrystallized from ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][CH2:14][C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)C.[Ni]>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCOc1cccc(OCc2ccccc2)c1
Agent: [Ni]
Solvent: CC(C)O
Product: NCCCOc1cccc(OCc2ccccc2)c1
Yield: 69.5 %

Procedure:
A mixture of 3-[m-(benzyloxy)phenoxy]-propionitrile (203 g, 0.80 mol) in 2-propanol is hydrogenated over Raney nickel catalyst (50 g). The catalyst is filtered, and the filtrate is evaporated. Distillation of the residue under high vacuum gives 143 g (69%) of product, bp 190° C. (0.15 mm).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[Cl:32].[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[Cl:32])[CH2:30][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(Br)c2)CC1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 140.2 ml (1.0 mol) of diisopropylamine were dissolved in 1200 ml of dry THF, and the mixture was cooled to −30° C. 400 ml (1.0 mol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 94.8 g (0.667 mol) of tert-butyl cyclopropanecarboxylate in 750 ml of THF was added to the reaction solution, and during the addition the temperature was kept below −60° C. After 4 h of stirring at −60° C., a solution of 208.6 g (0.733 mol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 550 ml of THF was added, and once more the temperature was kept below −60° C. during the addition. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added carefully. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 95.5 g (41.4% of theory) of the title compound.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].C(OP([CH2:19][C:20]#[N:21])(=O)OCC)C.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[N:35]=[C:34]([C:36]3[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=3)[CH:39]=O)[CH:33]=[N:32][CH:31]=2)[CH2:25][CH2:24]1>C1COCC1>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[N:35]=[C:34]([C:36]3[CH:37]=[C:38](/[CH:39]=[CH:19]/[C:20]#[N:21])[CH:41]=[CH:42][CH:43]=3)[CH:33]=[N:32][CH:31]=2)[CH2:25][CH2:24]1
Reactant: CN1CCCN(c2cncc(-c3cccc(C=O)c3)n2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CN1CCCN(c2cncc(-c3cccc(/C=C/C#N)c3)n2)CC1
Yield: 62 %

Procedure:
1-(6-Chloro-pyrazin-2-yl)-4-methyl-[1,4] diazepane (360 mg, 1.59 mmol), (intermediate C prepared in example 3), 3-formylphenylboronic acid (235 mg, 1.58 mmol) and bistriphenylphosphinepalladium(II)chloride (21 mg, 0.03 mmol) were dispersed in 10 mL DMF in a reaction tube. Subsequently 1.5 mL of 2M Na2CO3 was added. The tube was sealed and the reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was then filtered through a plug of celite, diluted with ethyl acetate and water (25 mL), and the organic phase was separated. The aqueous phase was extracted with 2×10 mL ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated. The residue was purified by flash chromatography. Intermediate L (337 mg, 72%; MS analysis electrospray, 297, M+H) was isolated by concentration of the solvents and used directly. Sodium hexamethyldisilazane (0.22 mL, 1M in THF, 0.22 mmol) was added to a solution of cyanomethyl-phosphonic acid diethyl ester (0.034 mL, 0.21 mmol) in 1 mL THF under an atmosphere of N2. The mixture was stirred for 2 h after which time a solution of 3-[6-(4-methyl-[1,4] diazepan-1-yl)-pyrazin-2-yl]-benzaldehyde in 2 mL THF was added. After 15 min. the solvents were evaporated and the residue was diluted with 5 mL water and extracted with ethyl acetate (2×5 mL). The organic extracts were combined, washed with brine, dried and concentrated. The residue was purified by flash chromatography to provide the title compound (40 mg, 62%); MS analysis electrospray, 320 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)ccc1C(=O)OC
Yield: 99.3 %

Procedure:
A mixture of methyl 4-chloro-2-hydroxybenzoate (2f) (96.3 g, 0.52 mol), allyl bromide (134 ml, 1.55 mol) and ground potassium carbonate (107 g, 0.77 mol) in 1500 ml of dry acetone was heated under reflux for 20 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide evaporated to dryness to give 3f (117 g, 99.6% yield) as a yellow solid, mp 47°-55° C. NMR (CDCl3) δ 7.73 (d, 1H, J=8 Hz, aromatic proton meta to Cl), 6.97 (m, 2H, aromatic protons alpha to Cl), 6.40-5.17 (m, 3H, olefinic orotons), 4.57 (m, 2H, CH2) and 3.90 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12]>C1CCCCC1>[CH3:1][C:2](=[N:12][NH:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCCCC(C)=O
Solvent: C1CCCCC1
Product: CCCCCCC(C)=NNC(=O)OC(C)(C)C

Procedure:
40 g (312 mmol) of 2-octanone and 41.23 g (312 mmol) of tert-butyl carbazate are refluxed for 2 hours in 350 ml of cyclohexane. The solvent and water are removed in vacuo. This gives 74.10 g (98%) of a waxy solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:28])[C:9]=1[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=O.CC(C)([O-])C.[K+]>C1COCC1>[CH3:16][O:15][C:13]([CH:12]1[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[CH2:10][C:9]2[C:8]([Br:28])=[CH:7][S:6][C:5]=2[C:3]1=[O:2])=[O:14]
Reactant: COC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(Br)csc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)c2scc(Br)c2CN1Cc1ccc(OC)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3-{[(2,4-dimethoxy-benzyl)-methoxycarbonylmethyl-amino]-methyl}-thiophene-2-carboxylic acid methyl ester (13.3 g, 28.2 mmol), example 31-c, was dissolved in 277 mL of anhydrous THF and cooled to −15° C. in a brine dry ice bath. A solution of 62.0 mL of 1.0 M potassium tert-butoxide in THF was added slowly to cold solution, and the reaction mixture was stirred at −15° C. for 30 min. and then at room temperature for 2 hours. The reaction was quenched with 62.0 mL of 1N HCl and 500 mL ammonium chloride, and extracted twice with 600 mL of ethyl acetate. The organic fractions were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 12.4 g of a yellow froth. MS: (+) m/z 461.9, 463.9 (M+Na+, 79Br/81Br).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH:28]([C:32](O)=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:32]([CH:28]3[O:29][CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]3)=[O:33])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 4 h
Yield: 123.1 %

Procedure:
N-(3,4-Dichlorophenyl)piperazine-1-carboxamide hydrochloride (467 mg) and 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (347 mg) were dissolved in dry THF (10 mL) followed by addition of N,N-diisopropylethylamine (0.52 ml) and HATU (628 mg) and the reaction was stirred for 4 h. The solvent was evaporated under reduced pressure then redissolved in ethyl acetate (50 ml) followed by washing with sat. aqueous NaHCO3 (20 ml), 10% w/v citric acid (aq.) (15 ml) and brine (15 ml). The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (1:1 EtOAc:hexanes 1:1 to EtOAc neat) afforded the title compound (900 mg) as an impure foam contaminated with N,N,N′,N′-tetramethylurea. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7]C)=O.N1CCCN2CCCN=C12.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH2:26][CH2:25]1>C1(C)C=CC=CC=1.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]1)=[O:7]
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: CN1CCN(c2ccccc2CN)CC1
Agent: C1CN=C2NCCCN2C1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N

Procedure:
A solution of methyl 3-amino-4-methylbenzoate (commercially available) (1.609 g, 9.74 mmol), TBD (2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine) (0.678 g, 4.87 mmol) and (2-(4-methylpiperazin-1-yl)phenyl)methanamine (commercially available) (2 g, 9.74 mmol) in toluene (30 ml) was heated at reflux overnight. The reaction mixture was diluted with EtOAc and washed with sat.NaHCO3 and water. The organic portion was separated, dried (MgSO4) and concentrated in vacuo. The product was purified by chromagraphy on silica eluting with a gradient of 0-20% 2M NH3 in MeOH/DCM to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[C@@H:37]([OH:39])[CH3:38])[N:16]=3)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a solution of 3-{2-[2-((S)-1-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene}azetidine-1-carboxylic acid tert-butyl ester (127 mg, 0.23 mmol) in EtOAc (5 mL) and EtOH (5 mL) was added 20% Pd(OH)2/C (130 mg) and the resulting mixture stirred under an atmosphere of H2 for 18 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo affording the title compound (109 mg, 86%). LCMS (method A): RT 3.06 min [M+H]+ 549.4
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.BrC1C=CC=C(Br)N=1.FC1C=CC=C(NN)N=1.FC1C=CC=C(F)N=1.N(C1C=CC=C(C(F)(F)F)N=1)N.[Cl:47]C1C=CC=C(C(F)(F)F)N=1.N(C1C=NC=C(C(F)(F)F)C=1)N.FC1C=NC=C(C(F)(F)F)C=1.N(C1C(Cl)=C(Cl)N=C(Cl)C=1Cl)N.ClC1N=C(Cl)C(Cl)=C(Cl)C=1Cl>>[Cl:47][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1
Reactant: NNc1cccc(Br)n1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Brc1cccc(Br)n1
Agent: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Fc1cccc(F)n1
Product: NNc1cccc(Cl)n1

Procedure:
The following were prepared analogously and analyzed by nmr spectroscopy: 2-bromo-6-hydrazinopyridine, m.p. 112°-114° C. (from 2,6-dibromopyridine); 2-fluoro-6-hydrazinopyridine, m.p. 74°-76° C. (from 2,6-difluoropyridine); 2-hydrazino-6-(trifluoromethyl)pyridine, m.p. 62°-64° C. (from 2-chloro-6-(trifluoromethyl)pyridine; 3-hydrazino-5-(trifluoromethyl)pyridine, pale yellow solid (from 3-fluoro-5-(trifluoromethyl)pyridine); 4-hydrazino-2,3,5,6-tetrachloropyridine, m.p. 180°-181° C. (from pentachloropyridine).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[NH:16][CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37](OC(C)=O)=[O:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:37](=[O:38])[CH3:36])[CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reaction time: 16 h

Procedure:
To a solution containing 49 (200 mg, 0.41 mmol) in DCM (5 mL) was added Ac2O (65 mg, 0.63 mmol) and DMAP (5 mg, cat.) at ambient temperature. After 16 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 170 mg (78%) of crude 68 which was used without further purification. Mass spectrum, m/z [527] (M+H)+.
Reaction SMILES: ClC1C=CC=CC=1[CH:8]=[CH:9][C:10]1[N:11](CCO)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15](OC)=[CH:14][CH:13]=2.[C:24]1(=[O:30])[NH:28][C:27](=[O:29])[CH:26]=[CH:25]1>>[C:24]1(=[O:30])[C:25]2[CH:26]([CH2:8][CH2:9][CH:10]3[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]3)[C:27](=[O:29])[NH:28]1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2c(c1)cc(C=Cc1ccccc1Cl)n2CCO
Product: O=C1NC(=O)C2CCC3Nc4ccccc4C3=C12
Yield: 79 %

Procedure:
Reaction of 2-{2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-1H-indol-1-yl}ethanol (III; Ar=2-chlorophenyl, R10═CH2CH2OH) (44) prepared according to example 41 with maleimide according to the procedure described in example 68 gave 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-methoxy-4,5,6,1 Oc-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H, 3aH)-dione (IV; Ar=2-chlorophenyl, R10═CH2CH2OH) (45) in a 79% yield as an oily solid, which was used without further purification.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1>>[CH:1]1([O:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: Cc1ccc(CCO)cc1
Product: Cc1ccc(CCOC2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
246 grams of cyclohexene is added to a stirred slurry of p-methyl phenyl beta ethanol (408 grams) and 25 grams of Amberlyst® 15 cation exchange resin maintained at 110° C., over a 2 hour period. The reaction mass is then aged at 110° C. for an additional 3 hours whereupon it is cooled and filtered. The resulting solution is then heated at reflux with 80 grams of 30% aqueous sodium hydroxide. The reaction mass is then cooled and the resulting organic layer is washed with 1 liter of water. The organic layer is separated from the reaction mass and distilled through a 11/2"×12" Goodlow packed column to afford the following distillation fractions:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C)C=O>[CH3:30][O:29][N:28]([CH3:27])[C:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:13]
Reactant: CNOC
Reactant: Cn1nnc2ccc(C(=O)O)cc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nnn(C)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
3-Methyl-3H-benzotriazole-5-carboxylic acid (1.67 g, 5.6 mmol) was suspended in 25 ml N,N-dimethylformamide. 1,1′-carbonyldiimidazole (1.0 g, 6.2 mmol) was added and the reaction stirred at room temperature for 90 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (593 mg, 6.2 mmol) was added and the reaction stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was dissolved in saturated aqueous ammonium chloride solution and extracted three times with chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. Crude material was purified on Biotage Flash 40S silica gel column using chloroform/methanol gradient system (100:0 to 97:3, respectively) as eluent to afford 3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (1.01 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:23][C:22]=4[CH:32]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1ccc2oc(-c3ccccc3)nc2c1
Product: c1ccc(-c2nc3cc(COc4ccc(CCCn5ccnc5)cc4)ccc3o2)cc1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-phenylbezoxazole to give 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylbenzoxazole. The yield was 67%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 137-138° C.