Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]=[CH2:3].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.O1CCCC1>CN(C)C=O.C1C=CC=CC=1>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:4][CH:1]=[CH:2][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCNC(=O)c1ccccc1OCc1ccccc1
Agent: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccccc2-c2ccc[nH]2)cc1

Procedure:
2.7 g (10 millimoles) of o-benzyloxybenzoic acid allylamide in 20 ml of a 20% strength by weight solution of phosgene and toluene are stirred, in the presence of 2 drops of dimethylformamide, at room temperature overnight. The residue which remains after distilling off the toluene under reduced pressure at 40° C. bath temperature is taken up in 30 ml of tetrahydrofuran and the solution is filtered through glass wool and is introduced, in the course of 45 minutes, into an ice-cooled solution of 4.0 g (30 millimoles) of potassium tert.-butylate in 60 ml of a 1:1 (by volume) mixture of tetrahydrofuran and benzene, under argon as a protective gas. 10 minutes after completion of the addition, the solvent is distilled off under reduced pressure, the residue is partitioned between methylene chloride and water, and the aqueous phase is extracted twice with methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:28])[CH3:27]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:28][CH2:26][CH3:27])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCN
Solvent: c1ccccc1
Product: CCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.500 g, 1.37 mmol), and benzene (30 ml) as a solvent were placed into a round bottom flask (50 cc) and, after blowing ethylamine (0.900 g, 20.0 mmol) thereinto, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-ethyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.390 g, 69.4% yield).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[CH:11]([NH2:14])([CH3:13])[CH3:12]>O>[CH:11]([NH3+:14])([CH3:13])[CH3:12].[CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3]
Reactant: CC(C)N
Agent: O=C(O)CNCP(=O)(O)O
Solvent: O
Product: CC(C)[NH3+]

Procedure:
Glyphosate acid, 169.07 g, was reacted with 90 g of isopropylamine in 122 g of distilled water in a closed vessel to produce a isopropylammonium glyphosate salt solution. (The closed vessel was necessary because the reaction is exothermic and isopropylamine boils at about 25° C.) The pressure within the vessel at first increases and then decreases as the reaction proceeds. The product, a clear viscous liquid, is miscible with water in all proportions and has a pH of about 6.5.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH3:23])=[CH:18][CH:17]=[C:16]([C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH2:44].[H-].[Na+].Cl>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[N:40][CH:41]=[C:42]([Cl:45])[C:43]=1[NH:44][C:24]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[C:19]([O:21][CH2:22][CH3:23])=[CH:18][CH:17]=1)=[O:26]
Reactant: CCOc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 4-nitrophenyl 9-benzyl-6-chloro-1-ethoxy-9H-4-carbazolecarboxylate (31 mg, 0.062 mmoles) and 3,5 dichloro-4-aminopyridine (10.1 mg, 0.062 mmoles) in dry DMF (3 ml), under N2 atmosphere, 60% sodium hydride (5.40 mg, 0.124 mmoles) was added at 25° C. and the reaction mixture was stirred overnight. The reaction mixture was poured into ice-cold water and neutralized with 1N HCl. The compound was extracted with chloroform (3×10 ml), combined the organic layers and washed with water (3×10 ml) and with brine (10 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated to give 22.5 mg of the title compound as an off-white crystalline solid. m. p: 221-223° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH:28]=[C:27]([CH2:29][CH2:30][N:31]2C(=O)C3C(=CC=CC=3)C2=O)[N:26]=[C:25]1[C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CCO>[NH2:31][CH2:30][CH2:29][C:27]1[N:26]=[C:25]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:24]([CH:20]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=3)[N:10]=2)[CH:21]([CH3:23])[CH3:22])[CH:28]=1
Reactant: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: CCO
Product: Cc1ccc(-c2nc(CCN)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 5 °C
Yield: 44.1 %

Procedure:
A solution of 2-(2-{1-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-yl}-ethyl)-isoindole-1,3-dione (278 mg, 0.423 mmol) and anhydrous hydrazine (98 mg, 3.06 mmol) in EtOH (12 mL) was refluxed for 3.0 h. The reaction was cooled to 5° C. and a white precipitate was filtered off. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 90:9:1 methylene chloride:methanol:ammonium hydroxide as eluent) to provide the title compound as a white solid (98.2 mg, 45%). MS(ES+) m/e 526 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[NH:14][CH2:13][CH2:12][O:11][C:10]=3[CH:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[N:14]([C:24](=[O:26])[CH3:25])[CH2:13][CH2:12][O:11][C:10]=3[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc(-c2cnc3c(c2)OCCN3)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCOc2cc(-c3cncc(F)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To a solution of 7-(5-fluoro-pyridin-3-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (350 mg, 1.5 mmol) (which is synthesized according to the procedure for Step 1 of Example 12) in DCM (100 mL) is added pyridine (1.7 g 18 mmol), then acetyl chloride (710 mg 9.1 mmol) is added dropwise. The solution is stirred at room temperature for 16 hrs and the solvent is removed. The residue is purified by preparative HPLC to give 54 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32]C(OCC=C)=O)[C:27]=2[F:39])[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.O>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.ClCCl>[NH2:32][C:28]1[C:27]([F:39])=[C:26]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (855 mg, 1.489 mmol) was dissolved into dichloromethane (DCM) (8 mL). To this solution were added tributylstannane (433 mg, 1.489 mmol), tetrakis (86 mg, 0.074 mmol) and water (0.083 mL, 4.62 mmol), and the reaction mixture was stirred for 1 h and concentrated. The residue was purified using column chromatography (0 to 100% EtOAc/hexane) to give 690 mg of the title compound. MS (ESI): 490.1 [M+1]+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1.CN(C)C1C=CN=CC=1>[N:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[NH:42][C:38]=1[S:37][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Reactant: Sc1nc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reaction time: 1 h
Yield: 38.8 %

Procedure:
2-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (104.94 g, 0.286 mol) was dissolved in tetrahydrofuran (1.4 L), and triethylamine (48.5 g, 0.479 mol), 4-dimethylaminopyridine (1.76 g, 14.4 mmol), and methanesulfonyl chloride (42 g, 0.366 mol) were sequentially added to the solution under cooling with ice, followed by stirring for 1 hour at the same temperature. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure, to thereby yield 144.92 g of a pale yellow foamed substance. The product was dissolved in N,N-dimethylformamide (1 L), and 2-mercaptobenzimidazole (48.58 g, 0.323 mol), potassium carbonate (48.58 g, 0.351 mol), and 18-crown-6 (3.56 g, 13.5 mmol) were added to the resultant solution at room temperature, followed by stirring for 3 hours at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroforn and water. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: hexane/acetone=1/1-1/3), to thereby yield 55.85 g of 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (yield: 39.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1>>[N:46]1([CH2:49][CH2:50][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCN1CCOCC1
Product: COc1cc(C(=O)OCCN2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-morpholinoethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-ethyl ester. MS (ES+) m/z calcd. for C37H41Cl2F2N4O5: [(M+H)+]: 729. found: 729.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[CH:8][O:7][NH:6]1)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18]>C(O)(=O)C>[CH2:13]([O:12][C:10]([C:5]1([C:3]2[N:19]=[C:17]([NH:16][CH3:15])[S:18][CH:2]=2)[CH:9]=[CH:8][O:7][NH:6]1)=[O:11])[CH3:14]
Reactant: CNC(N)=S
Reactant: CCOC(=O)C1(C(=O)CBr)C=CON1
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2csc(NC)n2)C=CON1

Procedure:
A solution of ethyl 3-(bromoacetyl)isoxazole-3-carboxylate (100 mg, 0.40 mmol) and methylthiourea (69 mg, 0.76 mmol) in acetic acid (3.0 mL) was heated at 150° C. in the microwave for 15 minutes. Solvent was removed in vacuo to give the crude which was used without purification. MF=C10H11N3O3S; LCMS calculated for C10H11N3O3S; (M+H)+: m/z=254.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O>[F:14][C:13]([F:15])([F:16])[C:9]1[CH:8]=[C:7]([NH:6][CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Water (150 mL) and acrylic acid (48 g) were added to 3-aminobenzotrifluoride (75 g). The reaction mixture was stirred at 100° C. for one hour. The solution was cooled to room temperature. The pH of the solution was then adjusted to 10 with a 1 N aqueous sodium hydroxide solution. The solution was washed with diethyl ether, and the pH of the solution was then adjusted to 3 with 1 N hydrochloric acid. The solution was extracted with diethyl ether. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=2:1). The title compound (82 g) was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH2:4][O:5]C1CCCCO1>C(O)C>[OH:5][CH2:4][C:3]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=1)([CH3:12])[CH3:2]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: Cl
Solvent: CCO
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 54 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
2120 mL 10M HCl in ethanol is added to a mixture of 10.8 kg N-{3-[1,1-Dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide in 65 L ethanol at 51° C. The mixture is stirred for 2.5 h at 54° C. and then is cooled to 1° C. The suspension is filtered and the filter cake is washed once with 5 L cold ethanol and once with 7 L ethanol. Drying of the filter cake provides 8001 g product. ES-MS: m/z 375 [M+H];]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (6H, s) 1.59-1.72 (2H, m), 1.68 (6H, s), 1.80-1.86 (2H, m), 3.34-3.43 (4H, m), 3.85-3.94 (3H, m), 4.80 (1H, t, 3JH,H=5.5 Hz), 6.30 (1H, s), 11.27 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]3=[N:13][C:12]=2[CH3:21])=O)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>O1CCCC1>[CH3:21][C:12]1[N:13]=[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]2[C:11]=1[CH2:9][NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccnc(NC(=O)c2c(C)nc3cc(C)ccn23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccnc(NCc2c(C)nc3cc(C)ccn23)c1
Yield: 25 %

Procedure:
760 mg 2,7-dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid (4-methyl-pyridin-2-yl)-amide were added to a suspension of 160 mg lithium aluminium hydride in 12 ml tetrahydrofuran at room temperature. The mixture was then heated under reflux for 2.5 hours. After addition of an aqueous KOH solution, the resulting suspension was heated under reflux again for 15 minutes. After filtration, distillation of the solvent and purification by column chromatography, the product was obtained with a yield of 25%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH3:23])[C:5]2[CH2:10][O:9][C@@H:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:3]=[C:4]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH3:23])[C:5]4[CH2:10][O:9][C@@H:8]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:32][C:31]=2[O:37][CH3:38])[CH:29]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CC1CCCN1c1nc(Cl)nc2c1CO[C@H]2c1ccc(F)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(Nc2nc3c(c(N4CCCC4C)n2)CO[C@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
To a mixture of (S)-2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation Me) (192.0 mg, 0.575 mmol), 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (154 mg, 0.690 mmol), XANTPHOS (33.3 mg, 0.058 mmol), Pd2(dba)3 (26.3 mg, 0.029 mmol), and Cs2CO3 (562 mg, 1.726 mmol) was added Dioxane (2397 μL). The mixture was flushed with Nitrogen and placed in a capped vial and heated at 100° C. overnight. Cooled to rt and diluted with EtOAc. Filtered through a Celite® plug and rotovaped. The residue was placed on Silica Gel and eluted with an EtOAc/Hex gradient to obtain (S)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine (189 mg, 0.363 mmol, 63.1% yield) as a diasteriomeric mixture. The diasteriomers were separated by chiral SFC chromatography (Chiralcel OJ column, 40% MeOH (0.1% DEA) in CO2) to provide Examples 74A and 74B.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\CCCC(O)=O)[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C.C([N:36](CC)CC)C>>[OH:23][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH2:36])=[O:24]
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Product: NC(=O)c1ccccc1O

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2α, 0.306 ml. of triethylamine, 0.288 ml. of isobutylchloroformate, and 0.299 g. of o-hydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone-water (25:75:1). The residue obtained by concentration of selected fractions, 0.296 g., is crystallized from ethyl acetate diluted with 1.5 volumes of hexane as the title compound, white free-flowing crystals, m.p. 98.5°-100.1° C. having Rf 0.55 (TLC on silica gel in ethyl acetate-acetone (1:3)).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.C(OC([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=O)(C)(C)C>>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([N:25]([CH:22]2[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]2)[C:9](=[O:11])[C:8]2[C:3]([CH3:2])=[CH:4][CH:5]=[N:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1ccncc1C(=O)O
Agent: Cl
Product: COc1ccc(N(C(=O)c2cnccc2C)C2CCNCC2)cc1

Procedure:
Using general procedure F with 4-methylnicotinic acid hydrochloride (277 mg, 1.60 mmol) and 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 119) (350 mg, 1.14 mmol) and then using general procedure C afforded N-(4-methoxy-phenyl)-4-methyl-N-piperidin-4-yl-nicotinamide as a white solid (181 mg, 49% over 2 steps).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.6 mg, 0.166 mmol) in CH2Cl2 (2 mL) was added phenyl isocyanate (0.20 μL, 0.184 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 145 as a colorless solid (45.3 mg, 69%). LCMS m/z (%)=394 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (bs, 1H), 8.59 (bs, 1H), 7.48-7.41 (m, 4H), 7.37 (d, J=2.71 Hz, 1H), 7.29-7.23 (m, 2H), 7.09 (d, J=8.97 Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, J=1.85 Hz, 1H), 3.97 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])C)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[O-].[Na+].S(=O)(O)[O-:18].[Na+].Cl>>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:18])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])O
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of 1-(3,4-dihydro-2H-chromen-6-yl)ethanone (3.80 g, 22.0 mmol) and sodium hypochlorite [150 mL of a 6.0% aqueous solution, (Clorox brand of bleach)] in a 55° C. oil bath is stirred for 2 h. The mixture (now homogeneous) is cooled to rt and solid sodium bisulfite is added until a clear color persisted. HCl (ca 15 mL of a 6.0 M aqueous solution) is added, followed by extraction with EtOAc. The organic layer is washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3.10 g (82%) of chromane-6-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.55, 7.67, 7.6, 6.79, 4.20, 2.77, 1.96-1.90.