Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A solution of (2′,6′-dimethylbiphenyl-3-yl)methanol (1.0 g, 4.71 mmol), 5-hydroxyindole (0.63 g, 4.73 mmol) and tributylphosphine (1.5 mL, 6.02 mmol) in tetrahydrofuran (30 mL) was stirred, and 1,1′-(azodicarbonyl)dipiperidine (1.6 g, 6.34 mmol) was added by portions, and the mixture was stirred at room temperature for 18 hr. Diethyl ether (30 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (0.95 g, yield 62%) as a pale-brown oil.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[F:69])[C:63](Cl)=[O:64]>>[F:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[F:69])[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 139 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,4-difluoro benzoyl chloride.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:2][CH3:3].C(O[C:15](=[O:17])[CH3:16])(=O)C.N1C=CC=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1>[CH3:19][C:20]1[N:7]([CH2:8][CH2:9][CH3:10])[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:15](=[O:17])[CH:16]=1
Reactant: c1ccncc1
Reactant: CCCNC(=O)NCCC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CCCn1c(C)cc(=O)n(CCC)c1=O
Temperature: 95 °C

Procedure:
To a solution of N,N′ Dipropyl urea (10.0 g, 69.4 mmol) in pyridine (60 ml) was added acetic anhydride (21.6 ml, 229 mmol) and 4-(dimethylamino)pyridine (8.5 g, 69.4 mmol). The mixture was heated to 95° C. for 1.5 hours. The reaction mixture was cooled and the solvent was removed under vacuum. The residue was then dissolved in dichloromethane (200 ml) and washed with 2N HCl (2×60 ml) and saturated sodium bicarbonate (2×60 ml). The organic layer was concetrated and purified using column chromatography (2:1 Hexane:Ethyl Acetate) to yield 6-methyl-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione(4.0 g, M+1=210.92)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:36])[C:33](O)=[O:34])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:36])[C:33]([N:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[CH2:21][CH2:20][C:17]2[CH:18]=[N:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: Cc1n[nH]c2ccc(N)cc12
Product: Cc1n[nH]c2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)C(=O)c3ccc(F)cc3)cc12

Procedure:
In analogy to example 47 (steps 1-3), 3-Methyl-1H-indazol-5-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (4-fluoro-phenyl)-oxo-acetic acid were successively coupled to give after silica gel chromatography the target compound. MS(m/e): 471.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH2:1]([CH:3]([N:6]1[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[O:24][C:26]1=[O:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCC(CC)n1c(=O)oc2c(Oc3c(C)cc(C)cc3C)nc(C)cc21

Procedure:
The title compound was prepared as a grey solid by the method analogous to that described in the Example 21 starting from 4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol and triphosgene. 1H NMR (CDCl3) δ 6.87(s,2H), 6.55(s,1H), 3.98(m,1H), 2.29(s,3H), 2.28(s,3H), 2.09(s,6H), 1.9–2.05(m,2H), 1.8–1.9(m,2H), 0.90(t,6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:25])([F:24])[S:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])=[O:14].[Te]1C2C=CC=CC=2N=C1>ClCCl.C(Cl)(Cl)(Cl)Cl>[F:11][C:12]([F:25])([F:24])[S:13]([O-:16])(=[O:15])=[O:14].[CH2:17]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[Te:3][C:2]=1[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc2ccccc2[te]1
Reactant: O=S(=O)(OCc1ccccc1)C(F)(F)F
Agent: c1ccc2[te]cnc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1[te]c2ccccc2[n+]1Cc1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 18 h

Procedure:
2-Methylbenzotellurazole (Example 18) (0.81 g, 0.0033 mole) was dissolved in dichloromethane (25 ml). The solution of benzyl trifluoromethanesulfonate (0.004 mole) in carbon tetrachloride, prepared as described above, was placed in a dropped funnel and added at room temperature under a nitrogen atmosphere to the benzotellurazole solution. Stirring was continued for 18 hours at room temperature after the addition was complete, maintaining a nitrogen atmosphere. The solid was isolated by filtration, washed with diethyl ether, and dried at room temperature under a vacuum. Yield 0.30 g (19% of theory) of a white powder, m.p. 120°-122° C. The infrared, nuclear magnetic resonance, and mass spectra of this compound were in agreement with that expected for the structural formula.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH2:20]([O:23][CH2:24][CH2:25][NH2:26])[CH2:21][CH3:22].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:26][CH2:25][CH2:24][O:23][CH2:20][CH2:21][CH3:22])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CCCOCCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCNc1nc(NCCOCCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
100 mg (0.38 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 1.5 ml of acetonitrile, and 124 mg (0.76 mmol) of 2-propoxyethylamine hydrochloride and 196 mg (1.94 mmol) of triethylamine were added thereto, followed by stirring at 80° C. for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 91 mg (72.3%) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)CC1=O.C(=O)C1C=CC=CC=1.CN(C)CCN(C)C.C([Li])CCC.[CH3:49][S:50]SC>O1CCCC1.O>[CH3:49][S:50][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: O=C1Nc2ccccc2C1Cc1ccccc1
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: O=C1Cc2ccccc2N1
Agent: [Li]CCCC
Solvent: O=Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CSC1(Cc2ccccc2)C(=O)Nc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
3-Phenylmethyl-1,3-dihydro-2H-indol-2-one (4 g, 18.25 mmol) (prepared from 1,3-dihydro-2H-indol-2-one and benzaldehyde by the method of Daisley and Walker J. Chem. Soc. (C) (1971) page 1373) and tetramethylethylenediamine (4.5 g, 38.7 mmol) was dissolved in freshly distilled tetrahydrofuran under nitrogen and cooled to -75° C. in an acetone/dry ice bath. n-Butyllithium (2.5M, 20 ml, 50 mmol) was added and the mixture was stirred at -75° C. for 30 minutes. Dimethyl disulfide (1.65 g, 17.6 mmol) was added and the mixture was allowed to warm to room temperature. Water (5 ml) was added and the mixture was concentrated under reduced pressure to a yellow oil. Column chromatography on silica gel (eluent ethyl acetate/hexane) gave 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one as a yellow oil which solidified on standing.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH2:7]([O:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([N:24]([CH:27]([CH3:29])C)[CH2:25][CH3:26])(C)C>ClCCl.CN(C)C=O>[CH2:7]([O:15][CH:16]([O:5][CH2:1][CH3:2])[CH2:29][CH2:27][N:24]([CH2:25][CH2:26][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:18](=[O:20])[CH2:17][CH2:16][O:15][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(CCN(CCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Reaction time: 1 h
Yield: 115.4 %

Procedure:
Oxalyl chloride (0.078 g) was added dropwise to a solution of 3-phenethyloxypropanoic acid (0.10 g) in dichloromethane (10 mL), dimethyl formamide (1 drop) was added and stirring continued at room temperature for 1 hour. The mixture was subsequently concentrated, redissolved in dichloromethane (10 mL) and added dropwise to a solution of the crude 3,3-diethoxy-N-phenethyl-propan-1-amine, prepared as described in Example 8a) (0.33 g), and diisopropylethylamine (0.37 g) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 1 hour, diluted (dichloromethane, 50 mL), washed with water (2×20 mL), brine (20 mL), dried over magnesium sulfate and concentrated to give a crude product (0.32 g). The latter was purified by passing through a plug of SCX resin, eluting with methanol (100 mL) to give the sub-titled compound as a clear oil (0.127 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:26](=[O:30])/[CH:27]=[CH:28]/[CH3:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:28]([CH3:29])[CH2:27][CH:26]=[O:30])=[O:13]
Reactant: C/C=C/C=O
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(CC=O)P(=O)(O)CCCCc1ccccc1

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and crotonaldehyde (0.23 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. The chloroform was removed in vacuo. The residue was diluted with ether and extracted with 5% NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a solid which was dissolved in CH3OH; ether and hexane were added until turbidity. The mixture was kept in a freezer overnight, yield 0.099, m.p. 138° C.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:28])[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[CH3:29]O>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]23[O:28][C:5]([CH2:4][C:6]([O:8][CH3:29])=[O:7])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)=[CH:19][CH:20]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:28])[CH2:26][CH2:25][C:24](=[CH:4][C:6]([O:8][CH3:29])=[O:7])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: O=C1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=C1CCC(O)(c2ccc(Br)cc2)CC1
Product: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %
Yield: 12 %

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 70 mg, 1.7 mmol) in methanol (6.7 mL) was added trimethylphosphonoacetate (0.23 mL, 1.6 mmol) and the reaction was let stir at rt for 30 min. To the reaction was added 4-(4-bromophenyl)-4-hydroxycyclohexanone (360 mg, 1.3 mmol) and the reaction was let stir at rt for 20 h. The resulting reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 530 mg of a crude opaque oil. Purification of the crude material by column chromatography (25 g silica gel, 0-60% EtOAc:Hept, monitor 230 nm) afforded 51 mg (12%) of methyl 2-(4-(4-bromophenyl)-7-oxabicyclo[2.2.1]heptan-1-yl)acetate as a colorless oil (ESI-MS m/z: 327.1 [M+H]+, retention time 1.56 min (condition E)) and 275 mg (63%) of the title compound as a colorless oil (ESI-MS m/z: n/a [M+H]+, retention time 1.42 min (condition E)). 1H NMR (400 MHz, DMSO-d6): δ ppm 1.71-1.93 (m, 4H), 2.19 (d, J=13.1 Hz, 1H), 2.29-2.44 (m, 1H), 2.66 (td, J=12.6, 4.7 Hz, 1H), 3.56-3.69 (m, 4H), 5.24 (s, 1H), 5.72 (s, 1H), 7.41-7.52 (m, 4H). 13C NMR (100 MHz, DMSO-d6): δ ppm 166.1, 162.5, 148.7, 130.6, 127.1, 119.3, 112.6, 70.8, 50.6, 38.7, 32.4, 24.5.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C1(C)C=CC=CC=1.[CH3:31][S-:32].[Na+]>C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:32][CH3:31])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: C[S-]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
trans-N-Cyanomethyl-2-(4-fluorobenzenesulfonylmethyl)-cyclohexanecarboxamide (102 mg) was weighed into a 2.5 mL vial fitted with a stir vane and nitrogen inlet. Anhydrous toluene (1.5 mL) was added, followed by addition of sodium thiomethoxide (22 mg). The reaction mixture was heated to 70° C. and stirred overnight. After cooling to room temperature, the reaction mixture was stirred for two days. The reaction mixture was diluted with ethyl acetate (15 mL), washed with water and brine. The organic layer was removed, dried over magnesium sulfate and concentrated on a rotary evaporator. Chromatography of the crude product on C-18 reverse-phase HPLC provided the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][F:15])[CH:8]=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O.CO>[F:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(CCCCF)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CCCCF)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a mixture of 4-(4-fluoro-butyl)-pyridine-2-carboxylic acid methyl ester (0.24 g) in THF (3 mL) and water (1 mL) was added lithium hydroxide monohydrate (71.3 mg, 1.7 mmol, 1.5 equiv). The mixture was stirred at rt overnight and diluted with methanol (20 mL). Then H+ resin was added and the mixture was shaken for 10 minutes. The resin was washed with methanol (1×), 1:1 acetonitrile/water (1×), and acetonitrile (1×). The product was eluted with 5% TEA in methanol (4×) and acetonitrile (1×). The combined organic solvents were evaporated and co-evaporated with toluene to provide 4-(4-Fluoro-butyl)-pyridine-2-carboxylic acid (0.22 g, 65%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C>[F:17][C:10]1[CH:9]=[C:8]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[CH:15][C:11]=1[C:12]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1)=[O:14]
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)c(F)c2)s1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCCC3CN3CCCC3)c(F)c2)s1
Yield: 9.2 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 6 mL DMF using 4-(5-Cyano-thiophen-2-yl)-2-fluoro-benzoic acid (248 mg, 1.0 mmol), EDC-HCl (287 mg, 1.5 mmol), HOBt (203 mg, 1.5 mmol), DIEA (0.43 mL, 2.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (131 mg, 0.85 mmol) to give the title compound (30 mg, 10% yield). MS (ES+) 384.2 (M+H)+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:15]([NH2:16])=[C:14]([CH3:22])[CH:13]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCO>[Br:11][C:12]1[CH:13]=[C:14]([CH3:22])[C:15]2[NH:16][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH3:9])=[N:19][C:17]=2[CH:18]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: COc1ccccc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc2cc(Br)cc(C)c2[nH]1
Temperature: 80 °C
Yield: 79 %

Procedure:
o-Anisaldehyde (0.105 ml, 0.866 mmol) and 4-bromo-2-methyl-6-nitroaniline (0.2 g, 0.866 mmol) in EtOH (3.46 ml) were treated with solid sodium dithionite (0.535 g, 2.60 mmol) and the mixture was heated to 80° C. for 16 hours following the procedure of D. Yang et. al. (Synthesis 2005, 47-56). The reaction mixture was taken to dryness and partitioned between ethyl acetate and 2N NH4OH(aq). After the usual work-up the crude material was purified by silica gel chromatography (Biotage 25S, 20% -40% ethyl acetate in hexanes) to obtained 159 (0.217 g, 0.684 mmol, 79% yield) as yellow solid. LRMS (ESI): (calc.) 316.0 and 318.0 (found) 317.1 and 319.1 (MH)+.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=[C:16]([NH2:28])[C:15]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:14]1[N:19]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=[C:16]2[C:15]=1[NH:29][C:2](=[O:4])[NH:28]2
Reactant: Nc1nc(SCc2ccccc2)nc(Cl)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
A solution of triphosgene (0.92 g) in DCM (25 ml) was added dropwise to a solution of the product from example 2, step (e) (0.69 g) and triethylamine (0.55 ml) in DCM (25 ml) at −10° C. The cooling bath was then removed and the suspension stirred for 2.5 h. Upon cooling to 0° C. NaHCO3 (20 ml) was added with vigorous stirring before recovering the organics by extracting with DCM (3×50 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to yield a crude yellow solid. This material was triturated with EtOAc and filtered to afford a pink solid (360 mg, 48%). The filtrate was concentrated and again triturated with EtOAc to provide a second crop (170 mg, 70% overall)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:36]([CH3:37])=[CH:35][C:34](O)=[CH:33][C:32]=1[CH3:39].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:32]([CH3:39])=[CH:33][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:35][C:36]=1[CH3:37]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1c(C)cc(O)cc1C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1c(C)cc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1C
Yield: 12 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-hydroxy-2,6-dimethyl-benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 60:40) to give the desired compound as a light yellow solid (12%). MS (Turbo Spray): m/z=553.3 [M+H].