Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([C:19]3[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[C:2]1([NH:1][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[NH:27][C:26]5[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=5[CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccccc5)nc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A dark red mixture of aniline (0.077 ml, 0.840 mmol), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.050 g, 0.168 mmol) and LHMDS (1.0 M solution in THF; 0.840 ml, 0.840 mmol) was sealed and stirred at RT for 1 h. The reaction was then partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting material was suspended in 1 mL MeOH, sonicated for 1 min, filtered, and rinsed 2× MeOH. The solid was dried in vacuo to give 2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.035 g, 0.099 mmol, 59% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.18 (1H, br. s), 9.52 (1H, s), 8.11 (1H, d, J=9.0 Hz), 7.94 (1H, dd, J=7.4, 1.6 Hz), 7.62-7.70 (2H, m), 7.55-7.61 (1H, m), 7.36-7.45 (2H, m), 7.28 (1H, t, J=7.7 Hz), 7.04-7.14 (2H, m), 6.87-6.95 (2H, m), 3.35-3.44 (2H, m), 2.59-2.69 (2H, m). m/z (ESI, +ve) 355.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])[CH2:3][O:4]CC1C=CC=CC=1.C1(C)C=CC=CC=1.CS(C)=O>C(N(CC)CC)C>[OH:4][CH2:3][C:2]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])=[O:1]
Reactant: COc1ccc(OCC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(O)COCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(OCC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)CO)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
A sulfur trioxide-pyridine complex (716 mg) was added, under ice-cooling, to a solution of (S)-2-[[(S)-2-(1-hydroxy-2(phenylmethyloxy)ethyl]-1-pyrrolidinyl]carbonyl]-1-[(4methoxyphenyl)oxyacetyl]pyrrolidine (988 mg) in a mixed solvent of toluene (1 ml), DMSO (1.5 ml) and triethylamine (0.7 ml) and the mixture was stirred for 2.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of citric acid, saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (673 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]1([CH3:13])[CH:12]=[CH:11]C=[CH:9][CH:8]=1.F[C:15]1C([B-](C2C(F)=C(F)C(F)=C(F)C=2F)(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.C[NH+](C)C1C=CC=CC=1.ClCCl>C1COCC1.C1(C)C=C(C)C=C(C)C=1>[CH2:2]([C:1]12[CH2:13][CH:7]([CH2:12][CH2:11]1)[CH:8]=[CH:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:15]
Reactant: C=CCCCC
Reactant: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: Cc1ccccc1
Agent: C[NH+](C)c1ccccc1
Solvent: Cc1cc(C)cc(C)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCC12C=CC(CC1)C2
Temperature: 120 °C

Procedure:
HxNB (8.94 g, 0.05 mol), diPhNB (16.1 g, 0.05 mol), 1-hexene (4.2 g, 0.05 mol) and toluene (142.0 g) were combined in a 250 mL serum bottle and heated to 120° C. in an oil bath to form a solution. To this solution were added [Pd(PCy3)2(O2CCH3)(NCCH3)]tetrakis(pentafluorophenyl)borate (Pd1446) (5.8E-3 g, 4.0E-6 mol) and N, N-dimethylanilinium tetrakis(pentafluorophenyl)borate (DANFABA) (3.2E-3 g, 4.0E-6 mol), each in the form of a concentrated dichloromethane solution After addition, the resulting mixture was maintained at 120° C. for 6 hours. The copolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 80° C. under vacuum After drying, 12.0 g was obtained (48%). The molecular weight of the copolymer was determined by GPC in THF solvent (polystyrene standard) to be Mw=16,196 and Mn=8,448. The composition of the copolymer was determined by 1H-NMR to be 54/46 HxNB/diPhNB. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5569 in TE mode and 1.5555 in TM mode at a wavelength of 633 nm. The dried copolymer was dissolved in sufficient mesitylene to result in a 10 wt % copolymer solution.
Reaction SMILES: [N:1]#[C:2]Br.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH2:21]([N:23](CC)CC)C>CC(C)=O>[O:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:2]#[N:1])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[C:21]#[N:23]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: N#CBr
Reactant: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1

Procedure:
A three necked flask equipped with a drip funnel, thermometer and stirrer was charged with 46.6 g of cyanogen bromide and 45.7 g of 2,2-bis(4-hydroxyphenyl)propane in 300 ml of acetone and cooled to a temperature of between -5° C. and +3°C. To the solution was added dropwise 43.5 g of triethylamine with stirring at a rate sufficient to maintain the inner temperature below 10° C. After the addition, the reaction mixture was stirred for an additional 2 hours at 10° C. and then filtered to remove white precipitates. The filtrate was poured into a large volume of water whereupon white crystals were precipitated. These crystals were recrystalized from ethanol to give 43.2 g (78% of theory) of the title compound. The product was identified by its NMR spectrum as well as by the absorption of the cyanato group at 2260 cm-1 in its IR spectrum.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.N1C=CC=CC=1.[OH-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[O:20]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][CH:5]=1
Reactant: Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 7.0 g sample of 2-[3-(4-aminophenoxy)-propyl]-1H-isoindole-1,3(2H)-dione monohydrochloride (Example 95) is added to 100 ml of pyridine, 2.2 ml of 10N NaOH and 2.5 g methanesulfonyl chloride. The mixture is stirred at room temperature for 6 hours and 1 hour on a steam bath. The reaction mixture is poured into 900 ml of cold water and stored at 0° C. for 18 hours. The precipitate is collected, washed with 200 ml of water and dried to give 6.5 g of solid. A 1.0 g sample is crystallized from 100 ml of boiling ethanol after treatment with activated carbon to give 0.6 g of solid, m.p. 176°-178° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C)C(=O)C>[N:15]1[CH:16]=[CH:17][C:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccncc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (4.28 g, 30.5 mmol) in N,N-dimethylacetamide (30 mL) was added thionyl chloride (3.63 g, 30.5 mmol) and the mixture stirred at -10° to -15° C. for one hour. 4-(4-Pyridylsulfonyl)benzenamine (4.77 g, 20.4 mmol) was added in one portion and the mixture stirred at room temperature overnight. The solution was poured into water, the yellow solid filtered and purified by flash chromatography (50% v/v ethyl acetate in methylene chloride). Evaporation of the eluent and trituration of the resulting solid with hot methylene chloride yielded the title propanamide (4.61 g, 60%) as an off-white solid; mp 255°-257° C. 1H-NMR (300 MHz, d6 -DMSO): 1.71 (s, 3H, CH3), 7.71 (s, 1H, OH), 8.01 (d, 2H, J=4.5 Hz, aromatic), 8.12 (d, 2H, J=7.1 Hz, aromatic), 8.19 (d, 2H, J=7.1 Hz, aromatic), 9.00 (d, 2H, J=4.5 Hz, aromatic), 10.61 (s, 1H, NH). MS (CI, CH4): 375(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:22]=[O:23])C1C=CC=CC=1.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CN(C=O)c1ccccc1
Reactant: Fc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1F
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 77.6 %

Procedure:
To a stirred solution of 194.5 g (1.70 mol) of 1,4-difluorobenzene in 2 of dry tetrahydrofuran at -60° C. was added dropwise over 45 mins 1.70 mol (2.2M in hexane) of n-butyllithium at a rate such that the temperature remained below -55° C. The reaction mixture was stirred for 45 mins at below -50° C. and 1.5 hr at -50° to -45° C. The solution was then cooled to -60° C. and a solution of 230 g of N-methylformanilide in 300 ml of tetrahydrofuran was added dropwise over 30 mins. The mixture was stirred for 1 hr at -50° C. and allowed to warm to -30° C. over 15 mins. The mixture was then poured into ice water, neutralized (pH 6-7) with 10% sulfuric acid and extracted three times with hexane. The extracts were washed once with lN sulfuric acid, once with saturated sodium chloride solution and concentrated to an oil. Distillation at 64°-65° C. (20 mm) provided 187.5 g (77.5%) of product.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:5][CH:4]([CH2:6][CH3:7])[CH2:3]1.[CH3:11]COCC>>[CH3:11][C:8]([C:2]1([CH3:1])[CH2:3][CH:4]([CH2:6][CH3:7])[CH2:5]1)=[O:10]
Reactant: CCC1CC(C)(C(=O)O)C1
Reactant: CCOCC
Product: CCC1CC(C)(C(C)=O)C1

Procedure:
A solution of 5.0 g (35 mmol) of 1-methyl-(3-ethyl)-cyclobutanecarboxylic acid (prepared in Example 2A) in 35 ml of dry ether was stirred with ice-bath cooling under an argon atmosphere and 40 ml of a 2 M solution of methyllithuim in ether was added thereto. The resultant mixture was stirred without cooling for 3 hr. This mixture was then quenched by pouring the mixture into a vigorously stirred solution of 30 ml of methanol and 70 ml of water. The aqueous phase was separated and extracted twice with ether. The combined ether extract was dried over anhydrous magnesium sulfate and evaporated. The residue was distilled at reduced pressure to yield 2.5 g of the title compound having the following physical characteristics:
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([CH2:37][OH:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=2[CH:24]=1.Cl>O1CCCC1.C(O)C>[OH:3][CH:4]([CH2:37][OH:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)=[CH:8][C:7]=1[C:23]1[CH:32]=[CH:31][C:30]2[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=2[CH:24]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(CC(O)CO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3CC(O)CO)ccc21
Temperature: 50 °C
Reaction time: 48 h
Yield: 95.7 %

Procedure:
1 ml (1 mmol) of an aqueous solution of sodium hydroxide (1 M) is added to a solution of 200 mg (0.41 mmol) of ethyl 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 5 ml of tetrahydrofuran and 2 ml of ethanol. The reaction mixture is stirred for 48 h while heating at 50° C. After the reaction mixture has returned to ambient temperature, 2 ml (2 mmol) of a solution of hydrochloric acid (1 N) are added. The medium is extracted with ethyl acetate. The organic phase is washed with water, and then dried over magnesium sulfate. After evaporation of the solvents, the product obtained is purified by crystallization from a heptane/diethyl ether mixture. 180 mg of 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid are obtained (beige solid, Mp=145° C., yield=96%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cnc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
In a falsk, 4.0 g of 2,3-dichloro-5-trifluoromethyl pyridine, 10 ml of dimethyl sulfoxide, 5.1 g of anhydrous potassium carbonate and 2.9 g of p-chlorophenol were charged. The flask was heated in an oil bath at 110° C. to react them with stirring for 2 hours. The completion of the reaction was confirmed by a gas chromatography. The reaction mixture was cooled and poured into suitable amount of water. The reaction product was extracted with methylene chloride and the extracted phase was washed with a diluted sodium hydroxide aqueous solution and then, with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure and the oily residue was distilled to obtain 4.4 g of the object compound having a boiling point of 124°-127° C./2.5 mmHg.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12].S(=O)(=O)(O)O.S(=O)(=O)(O)N.S(Cl)(Cl)=O>>[Cl:10][S:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1
Agent: NS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 120 °C

Procedure:
122.1 g (1.0 mol) of benzoic acid are introduced into a mixture of 349.5 g (3.0 mol) of chlorosulfonic acid, 20 g of 96% strength sulfuric acid and 1 g of sulfamic acid. The reaction mixture thus obtained is heated to 120° C. in the course of 3 hours and stirred until evolution of gas has ended. The mixture is then cooled to 70° C. and 119.0 g (1.0 mol) of thionyl chloride are added dropwise over the course of 2 hours. After it has been stirred at 80° C. for 30 minutes, the reaction mixture is added dropwise at 10° C. to ice water, and the precipitated crystals are filtered off with suction and washed with ice water. 232.1 g of 3-chlorosulfonylbenzoic acid (water content: 10%), corresponding to 208.9 g (94.7% of theory), calculated as dry material, having a melting point of 129°-131° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(C3CCN(CCc4ccccc4)CC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.3 %

Procedure:
A mixture of 5.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 4.6 g of (2-bromoethyl)benzene, 4.2 g of sodium bicarbonate and 50 ml of dimethylformamide was stirred at 60° for 3 hr and at ambient temperature for 14 hr. The reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo The residue was recrystallized twice from 2-propanol (one charcoal treatment) to yield 2.6 g (35%) of product, mp 163°-165° C.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]C1=O.[H-].[Na+].[N:13]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[CH3:35][N:36]([CH3:39])[CH:37]=[O:38]>>[CH2:28]([O:27][C:25]([N:13]([C:4]1([CH3:3])[C:9]2[C:35](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:36]([C:39]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[C:37]1=[O:38])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Product: CC1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
After 8.5 g (0.00385 mole) of the indolinone derivative obtained in the above Reference example 18 were dissolved in 60 ml of dimethylformamide and 1.92 g (0.00502 mole) of sodium hydride (a 62.7% mineral oil dispersion) were added to the solution under argon atmosphere under ice cooling, the mixture was stirred at 5° C. for 20 minutes. Next, to the mixture was added 13.6 g of dibenzyl azodicarboxylate, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into aqueous ammonia-ice, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saline solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate:hexane (1:3 to 1:1 v/v)) to obtain 20.4 g of the title compound as a colorless caramel-like product. MS (DI, m/z): 239 (M+)
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[N:25][CH:24]=[C:23]([N:27]=[C:28]=[O:29])[CH:22]=1>ClCCl>[N:25]1[CH:26]=[CH:21][CH:22]=[C:23]([NH:27][C:28]([N:2]2[CH2:3][CH:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=3)[CH2:5]2)=[O:29])[CH:24]=1
Reactant: O=C=Nc1cccnc1
Reactant: Ic1ccc(OC2CNC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
2-(Azetidin-3-yloxy)-5-iodo-pyridine hydrochloride (4.2 g, 13 mmol) was suspended in anhydrous dichloromethane (50 mL) and triethylamine (5.5 mL) was added. Pyridine-3-isocyanate (1.45 g, 11.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hr. The suspension solvents were removed in vacuo and the residue partitioned between ethyl acetate (400 mL) and sat. aqueous sodium bicarbonate solution (400 mL). The mixture was filtered through a pad of celite and the filtrate phases were separated. The organic phase was washed with sat. aqueous sodium bicarbonate solution (250 mL), then sat aqueous sodium chloride solution (250 mL) and dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a yellow solid which was purified by flash chromatography on silica gel (100 g), eluting with a 1:19 mix of 7N ammonia in methanol solution: dichloromethane. This affords the title compound (2.0 g, 42%) as a colourless solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[NH2:16][C:17]1[N:18]=[C:19](S(C)(=O)=O)[S:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[NH2:16][C:17]1[N:18]=[C:19]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[S:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1sc(S(C)(=O)=O)nc1N
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: Cl
Product: COC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N

Procedure:
Analogously to the preparation of Example 49A, 335 mg (1.42 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate hydrochloride and 3190 mg (2.84 mmol) of methyl 4-amino-2-(methylsulfonyl)-1,3-thiazole-5-carboxylate gave 158 mg (29% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[C:49]([Cl:51])[CH:50]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:47]4[CH:46]=[C:45]([Cl:44])[CH:50]=[C:49]([Cl:51])[CH:48]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cc(Cl)cc(Cl)c4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross-coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 3,5-dichlorophenylboronic acid yielded the title compound (80% yield) as a white foam. MS (ISP): m/z=719.4 [M+H]+ and 721.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][CH:9]([NH2:11])[CH2:8][CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][N:15]=1.O>CO>[Cl:13][C:14]1[N:19]=[C:18]([NH:11][CH:9]2[CH2:8][CH:7]3[N:3]([CH2:4][CH2:5][CH2:6]3)[C:2]([CH3:12])([CH3:1])[CH2:10]2)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][N:15]=1
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: CC1(C)CC(N)CC2CCCN21
Solvent: CO
Solvent: O
Product: CC1(C)CC(Nc2nc(Cl)ncc2C(N)=O)CC2CCCN21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-octahydro-5,5-dimethylindolizin-7-amine (0.65 g, 3.9 mmol) in MeOH (10 ml) was added to a stirred solution of 2,4-dichloropyrimidine-5-carboxamide (0.75 g, 3.9 mmol; prepared according to the procedure set forth in US patent application publication US20110130415, page 41) in MeOH (30 ml) and H2O (4 ml) at 0° C. under nitrogen. After complete addition, the mixture was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue partitioned between EtOAc (150 ml) and 1N NaOH (100 ml). The aqueous layer was extracted with EtOAc (1×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was dry-loaded on to basic alumina (Brockmann grade IV) and then purified by column chromatography on basic alumina (Brockmann grade IV) using CH2Cl2/MeOH (1:0 to 95:5) as eluent to give the product (550 mg).