Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7].N1C=CC=CC=1.[O-:33]S([O-])=O.[Na+].[Na+].[OH2:39]>[Os](=O)(=O)(=O)=O>[F:24][C:23]([F:26])([F:25])[C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:11][CH2:10][N:9]([S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:7])=[O:8])[CH2:14][CH2:13]2)=[CH:20][CH:19]=1)([OH:33])[CH2:22][OH:39]
Reactant: O
Reactant: C=C(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Reactant: O=S([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(CO)C(F)(F)F)cc2)CC1
Reaction time: 0.67 h

Procedure:
Osmium tetroxide (2.4 mL, 4 wt % solution in water, 0.40 mmol) was added to a stirring solution of 1-(2-thiophenylsulfonyl)-4-(4-(1-(trifluoromethyl)ethenyl)phenyl)piperazine (0.16 g, 0.40 mmol) and pyridine (4.0 mL) at room temperature. After 40 min, water (4.0 mL) and Na2SO3 (1.5 g, 12 mmol) were added sequentially, the mixture was partitioned between water (10 mL) and chloroform (25 mL). The layers were separated and the aqueous material was washed with chloroform (2×10 mL). The combined organic material was dried (Na2SO4) and purified via column chromatography (10 g of silica, 1% MeOH in CH2Cl2). The purified residue was partitioned between water (20 mL) and tert-butanol (20 mL). To this was added sodium sulfite (2.0 g), potassium carbonate (2.0 g), and methanesulfonamide (0.20 g) at room temperature. After 6 h, the reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate (25 mL) and the layers were separated. The organic material was washed sequentially with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), dried (MgSO4), and purified via column chromatography on silica gel (10 g of silica, 1% MeOH in CH2Cl2) to yield 3,3,3-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol as a mixture of enantiomers (0.088 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19].CC1C=CC=CC=1>C(O)(=O)C.O>[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1ncccn1
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(=Nc2ncccn2)CC1

Procedure:
A mixture of 34 parts of ethyl 4-oxo-1-piperidinecarboxylate, 20 parts of 2-pyrimidinamine, 8 drops of acetic acid and 90 parts of methylbenzene is stirred and refluxed for 28 hours with water-separator. The reaction mixture is evaporated, yielding 50 parts of ethyl 4-(2-pyrimidinylimino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:16]1[N:21]=[C:20](F)[CH:19]=[CH:18][CH:17]=1)([C:9]1[N:14]=[C:13](F)[CH:12]=[CH:11][CH:10]=1)[CH3:8].[CH:23]1[CH:28]=[CH:27][C:26]([P-:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[K+].[Cl-].[NH4+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:16]1[N:21]=[C:20]([P:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:26]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=1)([C:9]1[N:14]=[C:13]([P:29]([C:26]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(c1ccccn1)(c1cccc(F)n1)c1cccc(F)n1
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1ccccn1)(c1cccc(P(c2ccccc2)c2ccccc2)n1)c1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: -60 °C
Reaction time: 72 h
Yield: 132.3 %

Procedure:
14.0 g (48.0 mmol) of 6,6′-(1-(pyridin-2-yl)ethane-1,1-diyl)bis(2-fluoropyridin) were dissolved in 300 ml of tetrahydrofurane and cooled to −60° C. 200 ml (100 mmol) of potassium diphenylphosphide (0.5 M solution in tetrahydrofurane) were added and the mixture was stirred for three days at room temperature. The reaction was hydrolysed with 200 ml of saturated ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed two times with saturated ammonium chloride solution and dried with sodium sulphate. The solvent was removed under reduced pressure to yield 40 g (>100%) of crude product which was used in the next synthesis without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 46.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.036 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[SH:12])C.C[O-].[Na+].[CH3:17][O:18][C:19](=[O:28])[C:20]([NH:23][C:24](=[O:27])[CH2:25]Cl)([CH3:22])[CH3:21]>CO>[CH3:17][O:18][C:19](=[O:28])[C:20]([NH:23][C:24]([C:25]1[S:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[C:4]=1[OH:13])=[O:27])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cc(F)ccc1S
Reactant: COC(=O)C(C)(C)NC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1O
Yield: 70.7 %

Procedure:
To a solution of 1.00 g 5-fluoro-2-mercaptobenzoic acid ethyl ester in 10 ml methanol 0.81 g of sodium methoxide were added portionwise, followed by addition of 0.97 g 2-(2-chloro-acetylamino)-2-methyl-propionic acid methyl ester. After refluxing the reaction under argon-atmosphere for 0.5 h the resulting mixture was filtrated, 20 ml water and 1.25 ml of acetic acid were added and the precipitated product was collected by filtration, washed with water, dissolved in ethyl acetate and THF, dried over sodium sulphate, filtrated and concentrated in vacuo. The resulting crude product was crystallized from diethylether to yield 1.10 g 2-[(5-fluoro-3-hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=1[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CCOc1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-Ethoxy-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c10) the title compound is obtained as off-white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([OH:27])=[C:22]([Br:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:67][S:68]([N:71]1[CH2:76][CH2:75][CH:74]([CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH2:73][CH2:72]1)(=[O:70])=[O:69]>C1COCC1.CCOC(C)=O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([Br:28])[C:23]([OH:27])=[C:24]([Br:26])[CH:25]=3)[C:29]([N:80]3[CH2:79][CH2:78][CH:77]([CH:74]4[CH2:73][CH2:72][N:71]([S:68]([CH3:67])(=[O:70])=[O:69])[CH2:76][CH2:75]4)[CH2:82][CH2:81]3)=[O:30])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CS(=O)(=O)N1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 130 mg (0.21 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 80 mg (0.25 mmol) TBTU and 50 μL (0.27 mmol) ethyldiisopropylamine in 10 mL THF was stirred for 50 min at RT. Then 60 mg (0.24 mmol) 1-methanesulphonyl-[4,4′]bipiperidinyl were added and the reaction mixture was stirred overnight at RT. The reaction solution was diluted with 50 mL EtOAc, extracted twice with 30 mL 15% K2CO3 solution, the organic phase was separated off and dried over MgSO4. After the desiccant and solvent had been eliminated the residue was triturated with water and filtered. The solid was combined with 5 mL 1 M HCl and stirred overnight. Further purification of the crude product was carried out by chromatography (silica gel, gradient DCM to DCM/MeOH/NH3 50:45:5). The fractions containing the product were combined, evaporated down i.vac., triturated with DIPE, suction filtered and dried at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][NH2:25])=[CH:15]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:15]4[NH:14][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:23][CH2:24][NH:25]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=CC1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2(C3NCCc4c3[nH]c3ccccc43)CCC2)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)cyclobutanecarbaldehyde (30 mg, 0.154 mmol) and 2-(1H-indol-3-yl)ethanamine (27.7 mg, 0.17 mmol) were dissolved in dichloromethane (3 mL). Trifluoroacetic acid (88 mg, 0.771 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature over night. The 5% NaHCO3 solution was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed successively with 5% NaHCO3 solution and saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. Yield: 36 mg (oil, 0.107 mmol, 69%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 48.9 %

Procedure:
Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (30:1) gave 83 mg (49%) of product as a colorless hard foam.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13](=[O:20])[CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O.CCOC(C)=O>[CH2:21]([O:20][C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:12]=1)[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3cccnc32)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncccc12
Temperature: 25 °C
Yield: 49 %

Procedure:
1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3(2H)-one (234 mg, 0.815 mmol) was dissolved in ethanol (8 mL). A few drops of concentrated sulfuric acid were added, and the mixture was heated at reflux for 5 hours. The mixture was then allowed to cool to room temperature. The mixture was then diluted with EtOAc, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. Flash 40 Biotage (40S cartridge, DCM) afforded 3-ethoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (126 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 8.42-8.45 m, 1H), 7.95-7.99 (m, 2H), 7.83-7.87 (m, 1H), 7.20-7.25 (m, 2H), 7.11-7.17 (m, 1H), 7.06 (s, 1H), 4.03-4.11 (m, 2H), 2.34 (s, 3H), 1.45-1.50 (m, 3H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[CH2:15]([OH:19])[CH:16]([OH:18])[CH3:17]>C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:12])=[O:5].[C:8]([OH:13])(=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:18])=[O:12].[CH2:15]([OH:19])[CH:16]([OH:18])[CH3:17].[C:1]([O-:6])(=[O:7])[CH2:2][CH2:3][C:4]([O-:12])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: O=C1C=CC(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(O)CO
Product: O=C(O)/C=C\C(=O)O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 75 °C
Yield: 638.9 %

Procedure:
A three-liter reactor equipped as in Example 2 is charged with maleic anhydride (690 g) and succinic anhydride (230 g). The mixture is heated to 75° C. to melt the maleic anhydride, and propylene glycol (353 g) is added. The exothermic reaction is maintained at or below 130° C. for two hours. A 3000 mol. wt. polyoxypropylene triol (1027 g) and p-toluenesulfonic acid (2.3 g) are added. The mixture is heated at 190° C. until the acid number falls to 112 mg KOH/g. Propylene glycol (146 g) is added, and heating continues until the acid number is 38 mg KOH/g. After cooling, 2077 g (86.8% yield) of resin is collected. GPC results: Mn=1982, Mw=10,730. A blend of the resin with 40% styrerie has APHA color=65.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 1.06 g of 3-[(1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 586 mg of methanesulfonyl chloride, and 518 mg of triethylamine in 19 ml dichloromethane give ((1-{5-carbamoyl-4-[1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: Br.[NH2:2][C:3]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>C(Cl)Cl>[NH2:2][C:3]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:7]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CN(C)CCN
Agent: Br
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cc(Br)cnc1N
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a suspension of 2-amino-5-bromo-nicotinic acid hydrobromide (4.00 g, 13.4 mmol) in CH2Cl2 (150 mL) was added Et3N (2.79 mL, 20.1 mmol), EDC (2.70 g, 14.1 mmol), and HOBt (1.91 g, 14.1 mmol) at 0° C., and the mixture was stirred for 10 min. N,N-dimethylethylenediamine was then added, and the mixture was allowed to stir overnight at room temperature. The organic solution was washed with 2 N NaOH (2×20 mL), H2O (2×20 mL) and brine, dried over Na2SO4 and filtered. The solvent was concentrated to give the title compound (2.70 g, 70%) as a yellow solid: MS (ESI) m/e 287 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9]C(=O)C)(=[O:3])[CH3:2].O.C(OC(OC(=O)C)CCC)(=O)C.O1CCCC1>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCOC(C)=O
Agent: CCCC(OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCCO
Yield: 0.3 %

Procedure:
The tube reactor is charged with 85 grams of silica-magnesia catalyst (70% silica -- 30% magnesia, 3/16 inch × 3/16 inch pills, Davison Chemical) and maintained at 220°-250° C. As in Example 1, 50.0 grams of 1,4-butanediol diacetate and 50 ml. of water are copassed over one hour. The effluent contains, as shown by quantitative glpc analysis, 12.2 grams of the unconverted butanediol diacetate (24% recovery), 15.1 grams of tetrahydrofuran and 24.4 grams of acetic acid (96% and 93% yields, respectively, based on 76% conversion), and 0.1 grams of 4-acetoxybutanol (0.3% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[Cl:1][C:2]1[N:7]=[C:6]([O:22][CH2:21][CH2:20][O:19][CH3:18])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: COCCO
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Agent: [Na]
Product: COCCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of 44.6 g (0.176 mol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine from Example 1 in 300 ml of 2-methoxyethanol at 0°-5° was added dropwise over 2 hours a solution of 4.25 g (0.177 g-atom) of sodium metal in 250 ml of 2-methoxyethanol. The solution was stirred for 30 minutes at 5°, concentrated and the resulting oil dissolved in 500 ml of ethyl acetate. The solution was washed with water, dried over sodium sulfate, filtered and concentrated to give 40.4 g (0.137 mol, 78%) of 2-chloro-4-(2-methoxyethoxy)-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine: m.p. 50°-52°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CO.ClCCl>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid piperidine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with 1% methanol/dichloromethane, 1.5% methanol/dichloromethane, 2% methanol/dichloromethane, and then 2.5% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1.Cl[C:29]1[N:34]=[C:33]([Cl:35])[C:32]([C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=1.[NH2:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:49][P:50](=[O:57])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])=[N:45][C:46]=1[O:47][CH3:48]>>[Cl:35][C:33]1[C:32]([C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=[C:29]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:49][P:50](=[O:57])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])=[N:45][C:46]=2[O:47][CH3:48])[N:34]=1
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)n1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)n1)OCC
Yield: 61 %

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 2,4-dichloro-5-trifluoromethylpyrimidine and diethyl [(5-amino-6-methoxypyridin-2-yl)methyl]phosphonate (Compound 286B). The crude material was purified by column chromatography (methylene chloride:CH3CN=0-20%) to obtain a mixture of 2 regioisomers with a ratio of roughly 4:1 (the major one is the desired title compound [364 mg, 61% yield]). 1H NMR (400 MHz, DMSO-d6) δ=1.22 (t, J=6.9 Hz, 6 H), 3.35 (d, J=21.7 Hz, 2 H), 3.87 (s, 3 H), 4.00-4.07 (m, 4 H), 6.98 (dd, J=7.8, 2.8 Hz, 1 H), 7.83 (d, J=7.6 Hz, 1 H), 8.72 (s, 1 H), 9.90 (s, 1 H). MS (ES+): m/z 455.21 (100), 457.15 (33) [MH+]; HPLC: tR=1.41 min (UPLC, Analytical).