Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].Cl.[Cl:14]OC(C)(C)C>CO>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([Cl:14])[CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2]
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)c1cccnc1N
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 2-amino-nicotinic acid ethyl ester (3.60 g, 21.7 mMol) in methanol (100 mL) was treated with HCl gas via sparge tube for 5 minutes, causing the colorless solution to turn yellow. The solution was concentrated in-vacuo, then stripped from methanol (2×50 mL) to remove excess HCl. The residue was dissolved in methanol (100 mL), treated with tert-butyl hypochlorite (2.6 g, 23.8 mMol), and the mixture was allowed to stir overnight at room temperature. Analysis by TLC showed that some starting material remained, so additional tert-butyl hypochlorite (0.47 g, 4.3 mMol) was added, and stirring was continued overnight. Analysis by TLC showed that all starting material had been consumed. The solution was concentrated in-vacuo, the residue was taken up in methylene chloride (150 mL), washed with saturated sodium bicarbonate (3×50 mL), 5% aqueous sodium thiosulfate (3×50 mL), water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 20%–30% ethyl acetate/heptane, to yield 1.50 g of colorless solids as product. MS (AP+)=201 (M+H)+. Yield=35%.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C(S([O-])(=O)=O)CCCCCCC.[Na+]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Agent: CCCCCCCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 46 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of sodium 1-octanesulfonate. 624 mg Styrene and 732 mg methyldichlorosilane were introduced into a glass tube, and 40 mg of sodium 1-octanesulfonate were added. 0.9 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.4 wt % platinum content) was added. The tube was sealed and placed in a 100° C. oil bath where it was heated for 20 hours. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 71% and a phenethylmethyldichlorosilane yield of 46%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 18:1.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:17].[C:1]1([C:7]2[CH2:11][CH:10]([C:12]([O:14][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:13])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1CC(c2ccccc2)=NN1
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(OCc1ccccc1)C1CC(c2ccccc2)=NN1
Reaction time: 48 h

Procedure:
20 g. of (+)-4,5-Dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid is added at room temperature to a solution of 25 g. of thionyl chloride in 150 ml. of benzyl alcohol (prepared by adding the thionyl chloride to the benzyl alcohol at -5°) and allowed to stir for 48 hours. Hydrochloric acid is removed in vacuo and the remaining solution is poured into 250 ml. of anhydrous ether. The separated product is collected, washed with fresh ether, and dried to give (+)-4,5-dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid, phenylmethyl ester, hydrochloride (1:1).
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H].C([OH:38])C>>[CH2:18]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:38])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: [H][H]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
The general procedure of Example 11 is followed using 100 grams (0.19 mol) of dihexadecylamine (451 eq. wt., 88% secondary amine, 30.2 grams (0.44 mol) of 50% aqueous hydrogen perioxide solution and 400 ml of ethanol. After stirring for 48 hours, the reaction mixture is filtered to give the above-named product which is twice recrystallized from 500 ml of chloroform. The desired product is obtained in a yield of 29.4 grams (32%) as white needles melting at 97°-99° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([C:11]1([N:24]([CH2:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][C:36]=2[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]3[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[F:47])[CH3:25])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10]>ClCCl>[ClH:46].[Cl:46][C:42]1[C:41]([F:47])=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([CH2:26][N:24]([CH3:25])[C:11]4([C:9]([NH2:8])=[O:10])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[CH:28]=3)[N:33]=[CH:32][N:31]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Product: Cl
Reaction time: 1 h
Yield: 224.5 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a stirred solution of tert-butyl 4-(aminocarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-1-carboxylate (0.35 g, 0.612 mmol) in dichloromethane (1 ml) at room temperature. The resulting solution was stirred for 1 hour, concentrated to dryness and the residue re-dissolved in dichloromethane (1 ml). 4.0 M hydrogen chloride in dioxane (1 ml) was then added to give a white precipitate. This was collected by filtration, washed with diethyl ether (2×10 ml) and dried to a constant weight to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide hydrochloride (0.35 g, 100%), as a white solid; Mass Spectrum: (M+H)+ 473.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][OH:41])[CH:37]=[C:36]([CH2:42][OH:43])[CH:35]=1.[C:44]([OH:47])(=[S:46])[CH3:45]>C1COCC1>[C:44]([S:46][CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][OH:41])[CH:37]=[C:36]([CH2:42][OH:43])[CH:35]=1)(=[O:47])[CH3:45]
Reactant: OCc1cc(CO)cc(CO)c1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCc1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 33.5 %

Procedure:
To a solution of triphenylphosphine (577 mg, 2.2 mmol) in anhydrous THF (5 mL) was added diethyl azodicarboxylate (2.2 M in toluene, 791 μL, 1.7 mmol) dropwise at 0° C. After stirred at 0° C. for 50 minutes, a solution of 1,3,5-tri(hydroxymethyl)benzene (269 mg, 1.6 mmol, prepared by reduction of trimethyl 1,3,5-benzenetricarboxylate with lithium aluminum hydride in THF, co-evaporated with dry benzene and dried on high vacuum for couple hours before use) and thioacetic acid (108 μL, 1.45 mmol) in dry THF (4 mL) was added dropwise. After 1 hour, the ice/water bath was removed and the reaction was stirred at room temperature for 15 hours. The solvents were removed by rotary evaporation in vacuo. The residue was purified by flash chromatography to give 5-acetylthiomethyl-1,3-bis(hydroxymethyl)-benzene as colorless solid (110 mg). 1H NMR (400 Hz, CDCl3): δ 7.13-6.99 (m, 3H), 4.45 (apt, J=20.4 Hz, 4H), 3.98 (apt, J=20.4 Hz, 4H), 3.73 (bs, 2H), 2.24 (apt, J=20.4 Hz, 3H); MS (ESI): m/z 249.0 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([CH2:20][NH2:21])[N:9]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([CH2:20][NH:21][C:31]([C:23]2[NH:22][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:32])[N:9]=1
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: NCC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one (80 mg, 0.282 mmole) and indole-2-carbonyl chloride (53 mg, 0.30 mmol) were mixed in 5 ml of methylene chloride at room temperature. The homogeneous reaction mixture was protected from moisture and treated with 42 l (0.30 mmole) of triethylamine. Within five min., triethylamine hydrochloride precipitated. The reaction mixture was stirred at room temperatre overnight and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The resulting solid was collected, washed with water and dried over P2O5 at 70° C. In this way, 39 mg of the analytical product was obtained, m.p.: 315°-317° (d).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:35][S:36]([N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)(=[O:38])=[O:37]>CN(C)C=O.CCOC(C)=O>[CH3:35][S:36]([N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:6]5[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:17]4[N:16]=3)[CH:47]=2)[CH2:42][CH2:41][CH2:40]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)N1CCCc2ccc(N)cc21
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)N(S(C)(=O)=O)CCC5)nn23)cn1
Reaction time: 8 h
Yield: 47.2 %

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (95.0 mg, 0.254 mmol) was dissolved in N,N-dimethylformamide (3.00 mL). N,N-diisopropylethylamine (133 uL, 0.761 mmol) was added followed by 1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamine (80.4 mg, 0.355 mmol) and the reaction was stirred overnight. The reaction was taken up in EtOAc (25 mL) and washed three times with water (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-70% EtOAc/hex as the eluting solvent to obtain the title compound as a yellow solid (54 mg, 47%). m.p.=202-203° C.; LCMS (m/e) 451 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.46 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.53 (dd, 1H, J=2.2 and 8.7 Hz), 7.81 (s, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.19 (d, 1H, J=4.7 Hz), 7.10 (d, 1H, J=8.4 Hz), 7.02-6.93 (m, 2H), 3.93 (s, 3H), 3.74-3.68 (m, 2H), 2.99 (s, 3H), 2.79-2.72 (m, 2H), 1.97-1.88 (m, 2H).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)[OH:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C[Si](C)(C)c1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cncs1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A solution of 2-(trimethylsilyl)thiazole (6.12 g, 38.9 mmol) in THF (80 mL) was cooled to −78° C. and treated with a dropwise addition of nBuLi (2.5 M in hexanes, 15.6 mL, 39.0 mmol). The reaction mixture was stirred at −78° C. for 1 h before 4-fluorobenzaldehyde (4.59 mL, 42.8 mmol) was added dropwise. The stirred suspension was allowed to warm gradually to room temperature over 16 h, then treated with 100 mL of saturated aqueous ammonium chloride and 100 mL of EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 10-50% EtOAc/hexanes to afford the product as a white solid (4.09 g, 19.5 mmol, 50% yield). MS (M+H)+ 210.
Reaction SMILES: C1(=O)[O:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.CN(C=O)C.[CH3:14][N:15]([C:32]([F:48])([F:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42](CCl)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[S:16]([C:19]([F:31])([F:30])[C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])(=[O:18])=[O:17].[C:49]([O:52][CH2:53]C)(=[O:51])[CH3:50]>>[CH3:14][N:15]([C:32]([F:48])([F:47])[C:33]1([CH2:53][O:52][C:49](=[O:51])[CH2:50][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:37][CH2:38]1)[S:16]([C:19]([F:30])([F:31])[C:20]([F:29])([F:28])[C:21]([F:26])([F:27])[C:22]([F:24])([F:25])[F:23])(=[O:18])=[O:17]
Reactant: O=C1CCCCCO1
Reactant: CCOC(C)=O
Reactant: CN(C(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(F)(F)C1(COC(=O)CCCCCO)C=CC(c2ccccc2)=CC1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Epsilon-caprolactone (0.012 mol, 1.37 g) and (C4H9)4NOH (55% w/w in water, 0.012 mol, 5.66 g) were mixed and heated at 65° C. for 2 hr. Then, water was evaporated by a rotary evaporator. DMF (20 mL) and 4-(N-methylperfluorobutanesulfonamidomethyl)-4′-chloromethylbiphenyl (0.01 mol, 5.28 g) were added. The solution was stirred at 65° C. for 2 hr. The solution was diluted by ethyl acetate, washed by water, dried by anhydrous magnesium sulfate. Evaporation of solvent by a rotary evaporator gave 5.0 g of 4′-(N-methylperfluorobutanesulfonamidomethyl)-4′-(6-hydroxyhexanoyloxymethyl) biphenyl.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)(C)C>[CH2:2]1[CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)C1CCCCC1

Procedure:
One mole of 4-hydroxybenzoic acid was reacted with two moles of hydrogen in the presence of 5% palladium-carbon catalyst. This reaction was carried out in isopropyl alcohol at a temperature of 130°-140° C. and a hydrogen pressure of 20-40 kg/cm2 (gauge) After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to recover the solvent. The resulting residue was recrystallized from a mixture of benzene and hexane to obtain cyclohexane-4-carboxylic acid. This product had a melting point of 67.0°-68.0° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])=[C:35]=O.[CH3:49][C:50]1[CH:51]=[CH:52][C:53]2[CH:54]=[C:55]3[CH2:62][NH:61][CH2:60][CH2:59][N:56]3[C:57]=2[CH:58]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:61]1[CH2:60][CH2:59][N:56]3[C:57]4[CH:58]=[C:50]([CH3:49])[CH:51]=[CH:52][C:53]=4[CH:54]=[C:55]3[CH2:62]1)[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Cc1ccc2cc3n(c2c1)CCNC3
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4ccc(C)cc43)C2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting with 244 mg (0.5 mmol) of the iminophosphorane from Example 12A, 105 mg of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene and 100 mg (0.5 mmol) of 9-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 33A, the general procedure [M] gives 1 mg (1% of theory) of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:45](C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH3:45])[CH2:22][CH2:23]3)[S:17][C:10]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 20.0 mg, 0.0357 mmol), formaldehyde (8.68 mg, 0.107 mmol, 37%), NaBH(OAc)3 (37.9 mg, 0.179 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (19.1 mg, 93.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 573 (M). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.94 (dd, 1H), 7.61 (m, 2H), 7.38 (m, 1H), 7.21-7.28 (m, 4H), 6.46 (d, 1H), 2.99 (m, 2H), 2.91 (m, 1H), 2.34 (s, 3H), 2.06-2.17 (m, 4H), 1.94 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([NH:6][CH2:7][CH3:8])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:20][CH2:21][O:22][CH2:23][CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH2:24][CH2:23][O:22][CH2:21][CH2:20][CH3:11])[CH2:7][CH3:8])=[CH:4][CH:3]=1
Reactant: CCOCCBr
Reactant: O=C([O-])[O-]
Reactant: CCNc1ccc(Br)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCN(CC)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 4-bromo-N-ethylaniline (17.08 g) in DMF (100 ml) were added at room temperature potassium carbonate (17.1 g), sodium iodide (12.4 g) and 2-bromoethylethyl ether (10.2 ml), and the mixture was stirred at 90° C. for 24 hours. To the mixture were added 2-bromoethylethyl ether (5.0 ml), potassium carbonate (6.22 g) and sodium iodide (6.64 g), and the mixture was stirred for 2 days. To the mixture were added 2-bromoethylethyl ether (10.0 ml), potassium carbonate (17.1 g) and sodium iodide (12.4 g), and the mixture was stirred at 90° C. for 3 days. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:9) to give yellow oil of 4-bromo-N-(2-propoxyethyl)-N-ethylaniline (18.11 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[F:19][C:18]([F:21])([F:20])[O:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:23][CH:24]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 31.9 %

Procedure:
To a solution of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (200 mg, 0.64 mmol) and cis-4-aminocyclohexanol hydrogenchloride (367 mg, 3.19 mmol) in NMP (2.0 mL) was added NaHCO3 (268 mg, 3.19 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (80 mg, 32%) as a pale yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[N:15]=1.[C:31](=O)([O:35]CC)[O:32][CH2:33][CH3:34]>C1COCC1>[C:27]([O:26][C:24]([N:17]1[C:16]2[N:15]=[C:14]([CH2:13][C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)OCC
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of diisopropylamine (47.7 mL, 364 mmole) in dry THF (250 mL) at 0° C. was added n-BuLi (2.5 M in hexanes, 145.6 mL, 364 mmole) dropwise. After 15 min, this solution was added dropwise to a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (32.3 g, 130 mmole) and diethyl carbonate (56.8 mL, 481 mmole) in dry THF (400 mL) at −78° C. After 30 min, the mixture was quenched with saturated NH4Cl (500 mL), warmed to RT, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. Drying under high vacuum overnight gave the title compound (42.52 g, 102%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=7.5 Hz, 1 H), 6.96 (d, J=7.5 Hz, 1 H), 4.18 (t, 2H), 3.75 (m, 4 H), 2.72 (t, 2 H), 1.91 (m, 2 H), 1.52 (s, 9 H), 1.24 (m, 3 H); MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Yield: 79 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (85 mg, 0.19 mmol) and N-bromosuccinimide (37 mg, 0.21 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 80 mg of the title compound as a yellow solid. MS: (−) m/z 531.17, 533.12 (M-1, 79/81Br).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2CCCc3cncn32)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C1(c2ccc(C#N)cc2)CCCc2cncn21

Procedure:
In a manner analogous to that described in example 21, reaction of 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with ethyl chloroformate yields the title compound.