Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2>CN1CCCC1=O.O.Cl.[Fe](Cl)(Cl)Cl>[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)#[N:3]
Reactant: N#C[Cu]
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2cc(O)ccc2c1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Copper (I) cyanide (2.73 g, 0.03 mol) was added to a solution containing 5 g (0.022 mol) 6-bromo-2-hydroxynaphthalene in 25 ml of dry N-methyl-2-pyrrolidinone and refluxed at 200° C. under nitrogen for 1.5 h. The reaction mixture was cooled to 100° C., poured into a solution of iron(III) chloride (5.9 g) in water (91 ml) and concentrated hydrochloric acid (3.18 ml), and stirred at 60° C. for 30 min. The obtained mixture was extracted with ethyl ether. The ether layer was treated with charcoal, dried over anhydrous sodium sulfate, and then evaporated to dryness. The obtained solid was recrystallized from water to yield 2.04 g (54%) white solid. 1H-NMR (CDCl3, TMS, δ in ppm): 5.60 (s, 1H, --OH), 7.10-8.07 (m, 6, aromatic protons).
Reaction SMILES: [H][H].[C:3]1([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: C1=C(c2ccccc2)CCCC1
Solvent: C1CCOC1
Product: c1ccc(C2CCCCC2)cc1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
In Example 7, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 1-phenylcyclohexene as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 1-phenylcyclohexene, and phenylcyclohexane was obtained at 99% yield (See FIG. 6.).
Reaction SMILES: [C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:27]([F:30])([F:29])[F:28])[OH:26])([O:3]CC)=[O:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:14]2[C:13](=[O:25])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:27]([F:30])([F:28])[F:29])[OH:26])([OH:3])=[O:2]
Reactant: CCOC(=O)C1C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)NC1(O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C(C(=O)O)C(O)(C(F)(F)F)N2
Temperature: 90 °C
Yield: 31.6 %

Procedure:
A suspension of 3-carboethoxy-2-trifluoromethyl-2-hydroxy-4(3-nitrophenyl)-2,3,4,6,7,8-hexahydro-5(1H)-quinolone (7.02 g) in ethanol (40 ml) and water (40 ml) was treated with lithium hydroxide monohydrate (1.44 g). The mixture was heated at 90° C. for 30 minutes, diluted with water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed (water and brine), dried, filtered and the solvent stripped to yield a brown oil which was further purified by chromatography (ethyl acetate and ethyl acetate/methanol, 4:1). 3-Carboxy-2-trifluoromethyl-2-hydroxy-4-(3-nitrophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (2.07 g) was obtained as a white solid. NMR: 1.85 (m,2, CH2), 2.10 (m,2, CH2), 2.33-2.60 (m,3, CH2, CH), 4.21 (d,1, J=8.7, CH), 7.47 (m,2, Ar), 7.81 (s,2, OH or NH, Ar), 7.96 (m,1H, Ar); MS: m/z=400(M).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:24][C:25]([NH:27][CH3:28])=[O:26].C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.07 g, 0.22 mmol) and 2-chloro-N-methylacetamide (0.023 g, 0.22 mmol) in dry DMF (3 mL) in a sealable tube was added triethylamine (0.1 mL, 0.72 mmol) and NaI (0.01 g). The tube was sealed and heated for four hours at 80° C., then cooled and quenched by addition of water. The reaction mixture was extracted EtOAc, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (EtOAc:MeOH 99:1 to 97:3) gave 0.044 g of 2-{[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-amino}-N-methyl-acetamide as a foam. MS (M+H)=393.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[BH4-].[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCCc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9 mmol) in EtOH (20 mL) was added NaBH4 (1.6 g, 42.7 mmol) at rt, and the reaction was stirred for 30 min. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×50 mL). Organics were washed with brine (50 mL), dried (Na2SO4) and concentrated to give 1.9 g (94%) of the title compound as a brown oil. [M+H] calc'd for C10H11BrO2, 227, 229. found 227, 229.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:12])[CH:8]=2)[N:3]=1.[OH-].[NH4+:14]>>[I:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:14])[CH:11]=[CH:10]2
Reactant: [NH4+]
Reactant: Clc1ccc2cc(I)ccc2n1
Agent: [OH-]
Product: Nc1ccc2cc(I)ccc2n1
Temperature: 140 °C
Yield: 84 %

Procedure:
A suspension of 2-chloro-6-iodo-quinoline (1 g, 3.46 mmol) in ammonium hydroxide (28%, 20 mL) was heated at 140° C. for 3 days under pressure tube. After cooling, the solvent was removed by rotary evaporator. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-quinolin-2-ylamine (0.78 g, 84%) as a black solid. LC-MS m/e 271 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1
Solvent: CN(C)C=O
Product: S=C=Nc1ccc(N2CCN(C3CCCC3)CC2)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
A solution of 4-[4-(1-cyclopentyl)-1-piperazinyl]benzenamine (5.7 g, 22.4 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (4 g, 22.5 mmol) (Aldrich) in N,N-dimethylformamide (40 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 hr. then poured into ice-water (1500 mL), stirred for 30 min. then the precipitate filtered and washed with water and dried under vacuum to give 4-cyclopentyl-1-(4-isothiocyanatophenyl)piperazine (6 g, 93%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1.[CH2:38]1[O:41][C@H:39]1[CH3:40]>CO>[OH:41][C@@H:39]([CH3:40])[CH2:38][N:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][C:4]([NH:16][C:17]3[N:22]=[CH:21][C:20]4=[CH:23][CH:24]=[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]4[N:18]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:11][CH2:12]1
Reactant: COc1cc(CN2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Reactant: C[C@H]1CO1
Solvent: CO
Product: COc1cc(CN2CCN(C[C@H](C)O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
Into a 8-dram vial, N-{2-[2-(2-Methoxy-4-piperazin-1-ylmethyl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide (70 mg, 0.1 mmol), Methanol (5 mL) and (S)-(−)-Propylene Oxide (0.00818 g, 0.141 mmol) were added. The reaction was stirred at room temperature over the weekend. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-[2-(2-{4-[4-((S)-2-Hydroxy-propyl)-piperazin-1-ylmethyl]-2-methoxy-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (10 mg, 11%). LCMS (E/I+) 580.13 (M+H). NMR 1H (DMSO-d6)-8.99 (s, 1H), 8.05 (d, 1H, J=7.67 Hz), 7.96-8.01 (m, 1H), 7.80 (s, 1H), 7.64-7.69 (m, 1H), 7.52-7.58 (m, 2H), 7.80 (bs, 1H), 7.03 (d, 1H, J=4.69 Hz), 7.00 (d, 1H, J=4.69 Hz), 6.87 (bd, 1H, J=7.39 Hz), 4.00 (bs, 2H), 3.88 (s, 3H), 2.50-3.70 (bm, 17H), 1.05 (bs, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]3[N:20]=[C:21](S(C)(=O)=O)[N:22]=[C:18]3[N:17]=[C:16]([CH3:27])[CH:15]=2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[O-:28][CH2:29][CH3:30].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]3[N:20]=[C:21]([O:28][CH2:29][CH3:30])[N:22]=[C:18]3[N:17]=[C:16]([CH3:27])[CH:15]=2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(Nc2cc(F)c(C(F)(F)F)c(F)c2)n2nc(S(C)(=O)=O)nc2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3cc(F)c(C(F)(F)F)c(F)c3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 12 (0.29 g, 0.712 mmol) was added to sodium ethoxide (ALDRICH, 0.145 g, 2.136 mmol) in ethanol (5 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes. Solvent was removed under vacuum and the crude mixture was purified by flash chromatography (Si, eluting Hexane/EtOAc mixtures from 90:10 to 0:100%) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:15]([CH2:14][N:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]1=[O:12])#[N:16]
Reactant: N#CCBr
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCn1cc(C(F)(F)F)cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.0 g (0.02 mole) of 3-chloro-5-(trifluoromethyl)-2-pyridinol, 2.6 g (0.022 mole) of monobromoacetonitrile, and 4.0 g of potassium carbonate in 40 ml of dimethyl sulfoxide was prepared and stirred at ambient temperature for 3 hours. Water was then added and the light brown solid that formed was separated by filtration and dried to obtain 2.3 g (45 percent of theory) of the title compound: melting point, 84°-85° C. This product had infrared and nmr spectra compatible with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)C)#[N:2].C([SnH](CCCC)CCCC)CCC.[N-:33]=[N+:34]=[N-:35].[Na+]>C1(C)C=CC=CC=1.CO>[NH:2]1[C:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[C:6]3=[CH:13][C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[N:35][N:34]=[N:33]1
Reactant: CC(=C1C(=O)Nc2ccc(C#N)cc21)c1ccc[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[SnH](CCCC)CCCC
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(-c3nnn[nH]3)cc2C1=Cc1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 5-cyano-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (100 mg, 0,42 mmol) in toluene was treated with tributyltin hydride (0.68 g, 2.1 mmol) and NaN3 (0.39 g, 2.52 mmol). The reaction mixture was refluxed overnight. Concentration afforded a residue which was dissolved in methanol and left at ambient temperature overnight. An orange-colored solid formed, which was filtered and dried in vacuo to afford 5-tetrazol-5-yl-3-[(pyrrol-2-yl)methylene]indolin-2-one; (29 mg) as an orange solid; 1H NMR (400 MHz, DMSO-d6) δ 6.22 (s, 1H), 6.90 (s, 1H), 7.08 (d, 1H), 7.20 (s, 1H), 7.80 (m, 1H), 7.84 (s, 1H), 8.14 (s, 1H), 11.22 (s, 1H) ppm.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:16]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH:21]([C:26](OC)=[O:27])[CH2:20]1)(=[O:18])[CH3:17].[O-]CC.[Na+].O>C(O)C>[OH:27][C:26]1[C:21]2[CH2:20][N:19]([C:16](=[O:18])[CH3:17])[CH2:24][CH2:23][C:22]=2[N:14]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:11][CH:10]=2)[N:15]=1
Reactant: COC(=O)C1CN(C(C)=O)CCC1=O
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Yield: 61.8 %

Procedure:
1-(4-(Oxazol-5-yl)phenyl)guanidine (2.7 g, 13.35 mmol), methyl 1-acetyl-4-oxopiperidin-3-carboxylate (2.66 g, 13.35 mmol) and sodium ethoxide (0.946 g, 13.35 mmol) in ethanol (15 mL) were heated in a microwave reactor at 100° C. for 15 minutes. The reaction mixture was allowed to reach room temperature and water was added. The solid obtained was filtered, washed with water and dried in a vaccum oven yielding 1-(4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (2.90 g, 61.8%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:16]3[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH:28]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.O>[O:29]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:16]3[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH:28]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:6]=1)[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Yield: 68.1 %

Procedure:
A mixture of alpha-oxo-4-[[2-(9-phenanthrenyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.685 g) in hot tetrahydrofuran (100 mL) was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the aqueous solution was acidified with excess hydrochloric acid and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.45 g of alpha-oxo-4-[[2-(9-phenanthrenyloxy) ethyl]oxy]benzeneacetic acid as a colorless solid, mp 179°-180° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cccc(F)c1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(F)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-bromo-3-fluorobenzoic acid (300 mg, 1.37 mmol) in methanol (10 mL) at rt, was added SOCl2 (0.11 mL, 1.51 mmol) and the mixture was stirred at rt for 18 h. The solvent was distilled off under reduced pressure. The crude was basified by adding saturated aqueous NaHCO3 solution and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The obtained crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:32][C:33](=[O:49])[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)Cl)[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:35]([C:37]3[CH:38]=[CH:39][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:41][CH:42]=3)=[CH:34][C:33]([O:32][CH2:30][CH3:31])=[O:49])[CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)C=C(c1ccc(-c2ccccc2)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 8 %

Procedure:
The title compound was synthesized from 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester and 3-biphenyl-4-yl-3-chloro-acrylic acid ethyl ester using the procedure described in Example 18, step (d), in an 8% yield as a mixture of E/Z isomers.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[CH:5][C:6]2[N:10]([C:11]3[CH:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[NH:13][N:12]=3)[CH:9]=[N:8][C:7]=2[CH:19]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([N:10]3[C:6]4[CH:5]=[C:4]([NH:20][C@H:21]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[CH3:22])[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:19][C:7]=4[N:8]=[CH:9]3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1cc2c(cc1CN)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCc1cc2ncn(-c3cc(C4CC4)[nH]n3)c2cc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A round bottom flask was charged with 6-(aminomethyl)-3-(5-cyclopropyl-1H-pyrazol-3-yl)-N-((S)-1-(4-fluorophenyl)ethyl)-3H-benzo[d]imidazol-5-amine (Example 42; 0.10 g, 0.256 mmol) and acetic acid loaded TFP resin (1.0 mmol/g loading, 0.256 g, 0.256 mmol) in mixture of THF-DCM (1:1, 3 ml) at 0° C. The resulting solution was stirred vigorously at 0° C. for 1 hour and filtered through a Jones tube. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml). After removal of solvent, the residue was purified by column chromatography (EtOAc-MeOH=20:1) to give the title compound as an off-white solid (0.083 g, 75%). 1H NMR (400 MHz) 12.67 (s, 1H), 8.50 (m, 1H), 8.18 (s, 1H), 7.39 (m, 3H), 7.11 (m, 2H), 6.73 (s, 1H), 6.09 (d, J=6.0 Hz, 1H), 5.96 (s, 1H), 4.53 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 1.93 (m, 1H), 1.93 (s, 3 h), 1.47 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 432; Found: [M+H]+ 433.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:24](OC)(OC)(OC)[CH3:25]>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:24]1[CH3:25]
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Reactant: COC(C)(OC)OC
Product: Cc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Yield: 67.3 %

Procedure:
The general method described in Part C of Example 30 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (8.0 g, 25.4 mmol) by reaction with trimethyl orthoacetate (3.6 g, 30 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinoline (5.80 g) as a solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=2[CH3:49])[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=2[CH3:49])[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c(C)c1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4C)c3)c2cc1OC
Yield: 83.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate from Step A (120 mg, 0.33 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (141 mg, 0.25 mmol, 83%). 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.39 (s, 1H), 7.36 (t, 1H), 7.23-7.11 (m, 4H), 6.94 (d, 1H), 6.33 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH2:13][O:14][CH3:15])=[N:9][O:10][C:11]=1[CH3:12].C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1.O>[CH3:15][O:14][CH2:13][C:8]1[C:7]([B:20]([OH:21])[OH:19])=[C:11]([CH3:12])[O:10][N:9]=1
Reactant: COCc1noc(C)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCc1noc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
n-Butyl lithium (2.5 M in hexanes, 2.20 mmol) was added dropwise to 4-bromo-3-methoxymethyl-5-methyl isoxazole (412 mg, 2.00 mmol) in THF (8 mL) at −78° C. under nitrogen. After stirring at −78° C. for 30 min triisopropylborate (564 mg, 3.00 mmol) was added dropwise. The temperature was maintained at −78° C. for 2 h then the reaction was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was poured into a mixture of 1N hydrochloric acid and water (1:1, 100 mL) and stirred rapidly for 1 h. The organic layer was separated and the aqueous layer was extracted with ether (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was triturated with hexanes (30 mL) then dried under high vacuum to provide 89 mg (29% yield) of 3-methoxymethyl-5-methyl isoxazole-4-boronic acid as a waxy tan solid which was immediately carried forward to the next reaction: 1H NMR (300 MHz, CDCl3) δ ppm 4.74 (s, 2H), 3.37 (s, 3H), 2.74 (s, 3H), 2.60 (s, 2H).