Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18](O)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:19])[C:15]2[N:21]=[CH:22][CH:23]=[CH:24][C:14]=2[C:13](=[O:25])[N:12]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 68.6 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (116 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-trifluoromethyl)-4-biphenyl]-methyl}amino)-1-piperidinyl]propanoate (Int. B2) (150 mg, 1 equiv), HATU (151 mg, 1.2 equiv), DMF (2.72 ml) and DIPEA (0.17 ml, 3 equiv) was shaken at room temperature for 3.25 h. The reaction mixture was partitioned between ethyl acetate/methanol and aqueous sodium bicarbonate, the organic layer was brine-washed, dried and treated with activated charcoal (250 mg). Flash chromatography (silica, 3-4% methanol in DCM) gave ethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (178 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncccc2C(F)(F)F)cc1
Temperature: 140 °C
Yield: 83.1 %

Procedure:
A mixture of commercially available 2-chloro-3-trifluoromethylpyridine (64.83 g, 357 mmol), 4-methoxybenzylamine (56 mL, 429 mmol) and DIPEA (73.4 mL, 429 mmol) in n-butanol (100 mL) was refluxed (oil bath temp. 140° C.) for 3.5 days. Concentrated in vacuum, partitioned between 25% HCl and TBME, reextracted the organic layer twice with 25% HCl, the aqueous layer was made alkaline with 32% NaOH, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (105.21 g, >100%). Vacuum distillation gave the product as a colorless liquid (83.766 g, 83%, bp 139-141° C. at 1.4 mbar). MS (ISP) 283.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([S:13](Cl)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([S:13](=[O:15])(=[O:14])[NH:20][CH2:19][CH2:17][OH:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1c[nH]c(-c2ccc(Cl)cc2)n1
Reactant: NCCO
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(NCCO)c1c[nH]c(-c2ccc(Cl)cc2)n1
Yield: 20 %

Procedure:
To a solution of 2-(4-chlorophenyl)-4-chlorosulfonylimidazole (1.3 g 0.005 m) in dioxane (15 ml) was added ethanolamine (0.61 g 0.01 ml). After 15 minutes the dioxane was removed under reduced pressure (20 mm) to yield a gum. The gum was slurried with water to yield a solid. The solid was filtered and recrystallized from acetonitrile to give 400 mg of 2-(4-chlorophenyl)-4-(2-hydroxyethylsulfamoyl)imidazolemelting at 210°-212°. (20% yield).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.[Br:24][C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[N:28]=[CH:29][C:30]=1[Br:31]>ClCCl>[Br:24][C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH:23]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:36][CH:37]=2)[N:28]=[CH:29][C:30]=1[Br:31]
Reactant: C1=COCCC1
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1c(Br)c(Br)cnn1-c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A catalytic amount of pyridinium p-toluenesulfonate and 3,4-dihydro-2H-pyrane (0.8 mL, 8.89 mmols) were added to a dichloromethane (30 mL) solution of 4,5-dibromo-2-(4-hydroxyphenyl)-2H-pyridazin-3-one (1.03 g, 2.98 mmols), and stirred at room temperature for 2 hours, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous potassium carbonate. Concentrating the solvent under reduced pressure, the resulting residue was crystallized from mixed solvent of ethyl acetate and hexane to provide the title compound (1.1 g, 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:36])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:35])=[O:34])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[C:28]1([C@@H:17]([NH:16][C:11]2[O:12][C:13]([CH3:15])([CH3:14])[C:8]([CH3:36])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[S:9](=[O:34])(=[O:35])[N:10]=2)[CH2:18][CH2:19][OH:20])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(C)c1ccccc1
Yield: 67.5 %

Procedure:
Under inert gas, 50 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were initially charged in 4 ml of methanol and, with addition of 18 mg of 10% Pd/C, a gentle hydrogen stream was passed through for 1 hour. The reaction solution was concentrated by rotary evaporation and the residue purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution. Subsequently, this aqueous residue was extracted with ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (22.8 mg) with a molecular weight of 402.5 g/mol (C21H26N2O4S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C-]#N.[K+]>C(O)C.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([C:7]([CH:7]([C:6]3[CH:1]=[CH:2][C:3]4[O:11][CH2:10][O:9][C:4]=4[CH:5]=3)[OH:8])=[O:8])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2

Procedure:
A solution of piperonal (5 g) in ethanol (6.5 ml) was treated with a solution of potassium cyanide (0.5 g) in water (5 ml), then refluxed for 5 h. The resultant precipitate was filtered off, washed with water then crystallized from ethanol to give DC-0001B (2.24 g, 45%) as an off white crystalline solid.
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[NH2:17])[N:13]=[C:12]([Cl:19])[N:11]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[NH2:2].CO>O1CCOCC1.Cl>[ClH:19].[C:1]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][N:9]1[C:10]1[N:11]=[C:12]([Cl:19])[N:13]=[C:14]([C:16]([NH2:17])=[O:18])[CH:15]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(N)=O)nc(Cl)n2)C(C(N)=O)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cc(N2CCNCC2C(N)=O)nc(Cl)n1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-carbamoyl-4-(6-carbamoyl-2-chloropyrimidin-4-yl)piperazine-1-carboxylate (4.744 g, 12.33 mmol) in dioxane (25 mL) was added 4M HCl in dioxane (5.0 mL, 20.0 mmol). After stirring overnight the reaction was diluted with additional dioxane (25 mL) and 4M HCl in dioxane (5.0 mL, 20.0 mmol). After 5 h, MeOH (10 mL) was added. After stirring overnight more MeOH (10 mL) was added. After stirring one more night the reaction was evaporated in vacuo to give crude 6-(2-carbamoylpiperazin-1-yl)-2-chloropyrimidine-4-carboxamide hydrochloride. The crude hydrochloride salt was suspended in THF (50 mL). To this was added iPr2NEt (7.10 mL, 40.8 mmol) and methyl iodide (0.85 mL, 13.7 mmol). The reaction vessel was sealed and heated at 70° C. for 5 h. The reaction mixture was cooled and partitioned between EtOAc (100 mL) and water (50 mL). The organics were isolated and saved. 1N aqueous NaOH was added to the aqueous layer then it was extracted with EtOAc (100 mL). These organics were also isolated and saved. Once more, 1N aqueous NaOH was added to the aqueous layer then it was extracted with EtOAc (100 mL). The organics were isolated and combined with the other batches of organic extracts. The combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The solid residue was triturated with MeOH (5 mL), filtered, and washed with MeOH (1×2 mL). The solid was dried under vacuum at 40° C. to give 6-(2-carbamoyl-4-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxamide as a cream-colored powder (0.924 g, 3.09 mmol, 25% yield). LC/MS: m/z=299.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH:18]1([CH2:21][C:22](N(OC)C)=[O:23])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][C:22]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:23])[CH2:20][CH2:19]1
Reactant: CON(C)C(=O)CC1CC1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC2CC2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2-cyclopropyl-N-methoxy-N-methylacetamide. It is used in crude form in the following reaction.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:45])[CH2:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[O:35])=[CH:27][C:26]=3[F:46])[CH:16]=2)=[O:14])[CH2:10]1)(C(C)(C)C)(C)C.CO>>[F:46][C:26]1[CH:27]=[C:28]([NH:31][C:32](=[O:45])[CH2:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[O:35])[CH:29]=[CH:30][C:25]=1[O:24][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:16]=[C:15]([C:13]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)=[O:14])[S:23][C:22]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O[Si](C)(C)C(C)(C)C)C4)sc23)c(F)c1
Solvent: CO
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O)C4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a suspension of N1-(4-(2-(3-(tert-butyldimethylsilyloxy)azetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N3-(2-methoxyphenyl)malonamide 275 (179 mg, 0.268 mmol) in MeOH (18 mL) HCl (1N in dioxane, 0.54 mL, 0.54 mmol) was added dropwise and the mixture was stirred for 15 min at room temperature. The solvent was removed under reduced pressure, MeOH was added to the residue and concentrated, the residue was suspended in water and lyophilized affording 271 (104.6 mg, 0.18 mmol, 67% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.68 (s, 1H), 9.64 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.06 (dd, J=1.9 Hz, J=9 Hz, 1H), 7.94 (s, 1H), 7.89 (dd, J=12.9 Hz, J=2.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.46 (dd, J=1.6 Hz, J=8.8 Hz, 1H), 7.11-7.04 (m, 2H), 6.92 (m, 1H), 6.84 (dd, J=5.5 Hz, J=1 HZ, 1H), 6.90 (m, 1H), 4.59 (m, 1H), 4.36-4.31 (m, 2H), 3.88-3.84 (m, 4H), 3.67 (s, 2H). MS (m/z): (M+1) 551.0 (100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].Cl>>[ClH:34].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(C(C)(C)C)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(8.7 mg, 24%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-t-butylphenylsulfonyl chloride (24.9 mg, 0.11 mmol). HRMS-FAB+ for C25H27N2O2SF3.HCl, calculated MH+ (--HCl): 477.18237; found: 477.18134.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:23])=[C:10]([C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:19])[C:17]=2[F:18])[NH:11][CH:12]2[CH2:14][CH2:13]2)[CH2:4][CH2:3]1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>>[CH2:32]([O:31][C:29](=[O:30])[C:28](=[CH:27][N:11]([CH:12]1[CH2:13][CH2:14]1)[C:10]1[C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:19])[C:17]([F:18])=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]=1[CH3:23])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:33]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1c(NC2CC2)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Product: CCOC(=O)C(=CN(c1c(C)c(N2CCN(C)CC2)c(F)c(C)c1[N+](=O)[O-])C1CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
To 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline (1.65 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and the mixture is heated at 150° C. for 25 hours. After cooling, the reaction product is purified by silica-gel column-chromatography (dichloromethane : methanol=100 : 1) to give diethyl[N-cyclopropyl-N-[3-(4-methyl-l-piperazinyl)-4 -fluoro-2,5-dimethyl-6-nitrophenyl]aminomethylene]malonate (1.58 g). The product is dissolved in acetic anhydride (7.9 ml) and thereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C., followed by stirring for 30 minutes. The resultant mixture is poured into ice-water, neutralized, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure. Purification by silica-gel column-chromatography (dichloromethane : methanol =10 : 1) and recrystallization from ethanol--diethyl ether to give ethyl 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4 -oxoquinoline-3-carboxylate (28 mg), as yellow crystals, m.p. 146°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:11](Br)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[S:13][C:7]=2[C:6]=1[OH:22])=[O:4].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:11]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[S:13][C:7]=2[C:6]=1[OH:22])=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ncc2c(Br)c(-c3ccc(F)cc3)sc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(-c3ccc(F)cc3)c(-c3ccc(F)cc3)sc2c1O
Temperature: 120 °C
Yield: 50.6 %

Procedure:
3-Bromo-2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (0.34 g, 0.89 mmol), example 36-g, 4-fluoro-phenyl boronic acid (0.373 mg, 2.67 mmol), sodium methoxide (0.433 g, 8.01 mmol), and tetrakis(triphenylphosphine)palladium(0) (257 mg, 0.22 mmol) were suspended in 15 mL of 1,4-dioxane. The reaction mixture was heated at 120° C. for 30 min. using a CEM microwave reactor (CEM, Matthews, N.C.). The reaction mixture was diluted with ethyl acetate, and washed with saturated sodium bicarbonate and brine solutions. The organic fraction was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-60% ethyl acetate in hexanes to produce 0.179 g of a yellow solid. MS: (+) m/z 398.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (83.5% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.97, 7.46-7.42, 7.39-7.29, 6.97, 4.07-4.01, 3.89-3.67, 3.58-3.51, 3.36-3.32, 1.53-147, 0.76-0.69, 0.48-0.42, 0.10-0.06. 13C NMR (75 MHz, CDCl3) 6166.7, 163.9, 162.8, 160.6, 159.9, 145.4, 129.6, 129.5, 127.0, 119.7, 119.4, 114.8, 114.7, 114.4, 114.38, 112.5, 44.4, 44.5, 44.3, 41.3, 39.6, 34.4, 8.6, 4.1. MS (ES+) m/z 466.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH2:33]([NH:40][C:30]([C:29]1[C:22]2[C:21]([NH:20][C@H:18]([C:7]3[N:8]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:9](=[O:11])[C:10]4=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]4[N:6]=3)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=2[NH:27][CH:28]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Reactant: NCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)NCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (30 mg, 0.07 mmol), benzylamine (20 mg, 0.19 mmol) and diisopropylethylamine (50 μl, 0.29 mmol) were dissolved in DMF (1.5 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 50 μl) was added dropwise and the reaction mixture was stirred overnight at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 5% DCM/MeOH) to give 17 mg (46% yield) of the title compound as a white solid.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.N.[H][H]>[Pd].CO>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:4]([NH2:3])[CH2:5][CH2:6]2)([CH3:16])([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: CON=C1CCc2cc(C(C)(C)C)ccc21
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CCC2N
Temperature: 50 °C
Reaction time: 16 h

Procedure:
5-tert-Butyl-1-indanone O-methyloxime (4.37 g, 20.2 mmol) and 10% palladium on carbon (2.2 g) were combined in methanol (50 ml) and ammonia (10 ml) and placed in a Parr apparatus which was charged with hydrogen to 60 psi. The reaction was shaken at 50° C. for 16 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was treated with diethyl ether (100 ml) and extracted with hydrochloric acid (1N, 3×50 ml). The combined aqueous extracts were neutralized with sodium hydroxide (6 g) in water (25 ml) and extracted with diethyl ether. The organic extracts were combined, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound which was used without further purification in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][CH2:17][C:18]2=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCCc2c1[nH]c1ccc(OC)cc21
Temperature: 85 °C
Yield: 53.6 %

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (50.0 mmol, 8.73 g) and ethyl 2-oxocyclohexaneacetate (50.0 mmol, 9.21 g) in absolute EtOH (25 ml) was heated at 85° C. for 1 h. After cooling to room temperature the mixture was filtered and the solvent was evaporated. Column chromatography (5% EtOAc in toluene) gave crystalline ethyl 6-methoxy-1,2,3,4-tetrahydrocarbazol-1-ylacetate (7.7 g, 53%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[OH:1][CH2:2][C:3]1[O:8][C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(=O)c(O)c(CO)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(CO)oc(C)cc2=O)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 5.9 g of 6-hydroxymethyl-5-hydroxy-2-methyl-4-pyrone in 60 ml of dimethylformamide were successively added 6.2 g of potassium carbonate and 6.2 ml of p-methoxybenzyl chloride. The mixture was stirred at 70° C. for 2 hours. The reaction liquid was concentrated and 200 ml of water and 400 ml of dichloromethane were added to the concentrate. The organic phase was then washed with 200 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was then separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (300 g) to give 5.9 g of the title compound.