Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([O:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4](=O)[O:3]1.C(#N)C.[NH2:29][OH:30].O>C1(C)C=CC=CC=1>[OH:30][N:29]1[C:2](=[O:1])[C@H:6]([O:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:3]
Reactant: NO
Reactant: O=C(O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a 3-neck 5 L round bottom flask fitted with a mechanical stirrer and a teflon coated temperature probe was added (22) (2.79 mol) followed by acetonitrile (2 L). The suspension was cooled in an ice bath to 4° C., followed by the addition of 50% aqueous hydroxylamine (180 mL, 2.93 mol) over 1 h. The starting material gradually dissolved during the addition and the reaction mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (1 L) and washed with 1 N HCl (2×1 L). The organic phase was separated and concentrated in vacuo to afford a viscous red syrup. The syrup was then heated for two hours in toluene (2.5 L) at 100° C. with azeotropic removal of water. The syrup gradually dissolved and then the product crystallized. After cooling to room temperature the solid was collected by filtration, washed with 10% acetone in hexane (2×1 L) and dried in a vacuum oven to afford the title compound (23) (862 g, 2.43 mol, 87%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 5.85 (s, 2H), 7.45 (app. t, 4H), 7.65 (app t, 2H), 8.05 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.Cl.ClC1C=C2C(=CC=1)C=C(S(N1CC[N:51]([C:54](C3SC4C(C=NO)NC(N)CC=4N=3)=[O:55])CC1)(=O)=O)C=C2>>[C:54]([CH:29]1[NH:28][CH2:27][C:26]2[S:25][C:24]([C:22]([N:19]3[CH2:18][CH2:17][N:16]([S:13]([C:8]4[CH:7]=[CH:6][C:5]5[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=5)[CH:9]=4)(=[O:14])=[O:15])[CH2:21][CH2:20]3)=[O:23])=[N:32][C:31]=2[CH2:30]1)(=[O:55])[NH2:51]
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: NC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2C(C=NO)N1
Agent: Cl
Product: NC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1

Procedure:
In a similar manner to Referential Example 33 and Example B-24 by using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride as a starting material, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride and also 1-[(6-carbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine were obtained. 1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride:
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14](C)=[N:13]1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH2:48]([S:45]([N:42]1[CH2:41][CH2:40][CH:39]([C:30]2[C:29]3[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([C:16]5[CH:15]=[CH:14][N:13]=[CH:3][CH:2]=5)=[O:18])=[CH:26][CH:25]=4)[CH:28]=3)[NH:32][CH:31]=2)[CH2:44][CH2:43]1)(=[O:47])=[O:46])[CH3:49]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5ccncc5)cc4)cc23)CC1
Yield: 45.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(4-pyridinylcarbonyl)amino]methyl}phenyl)boronic acid (124 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (45.8%).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[C:5]([C:8](OCC)=[O:9])[S:6][CH:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[F:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1
Reactant: CCOC(=O)c1nc(CF)cs1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1nc(CF)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a solution of ethyl 4-(fluoromethyl)-1,3-thiazole-2-carboxylate (170 mg) in MeOH (5 ml) was added NaBH4 (68 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into saturated NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (114 mg) as a colorless oil.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH2:21]([O:23][CH2:24][CH:25]=[O:26])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:25]([OH:26])[CH2:24][O:23][CH2:21][CH3:22]
Reactant: Fc1cncc(Br)c1
Reactant: CCOCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOCC(O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (2.66 mL, 4.26 mmol) was added to a solution of diisopropylamine (0.607 mL, 4.26 mmol) in THF (10 mL) at −78° C. After 30 min, 3-bromo-5-fluoropyridine (0.500 g, 2.84 mmol) in THF (10 mL) is added dropwise. The mixture was stirred at −78° C. for 1 hr, and 2-ethoxyacetaldehyde (0.464 g, 4.26 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hrs. The reaction is quenched with a saturated aqueous NaHCO3 solution and the cooling bath was removed. The mixture was shaken with ethyl acetate and the organic phase is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography employing heptane-ethyl acetate (4:1) to give 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-ethoxy-ethanol. MS (ESI) m/z 266.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][CH:6]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:7](Cl)=[O:8].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]1([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:2]([CH3:4])([CH3:3])[CH2:1][C:7]1=[O:8]
Reactant: C=C(C)C
Reactant: O=C(Cl)C(Cl)CC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C1(Cl)CC(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 60.2 %

Procedure:
In an autoclave, 280 g of isobutylene are added under pressure to 122 g (0.5 mole) of 2,4,4,4-tetrachlorobutyryl chloride in 600 ml of cyclohexane. A solution of 51 g (0.5 mole) of triethylamine in 500 ml of cyclohexane is then pumped in at 65° C. The reaction mixture is then kept for 3 hours at 65° C. The precipitated hydrochloride of triethylamine is collected by filtration and the filtrate is concentrated. The resulting crystals are collected by filtration, affording 79.4 g of 2-chloro-2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutan-1-one with a melting point of 75°-76° C. (60% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:42]3[CH2:41][CH2:40][N:39]([C:45]4[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=4)[CH2:44][CH2:43]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (486 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24]I)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:27]#[N:28]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][C:27]#[N:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CCI
Reactant: CC#N
Agent: Cl
Product: N#CCCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 4-(4-chloro-benzenesulfonyl)-5,8-difluoro-3-(2-iodo-ethyl)-chroman (3.47 g, 6.94 mmol) in CH3CN (70 mL) was treated with n-Bu4NCN (2.2 g, 8.0 mmol). After 12 h, the reaction mixture was diluted with 1N HCl and extracted with Et2O (3×). The combined organic extracts were washed with 1N HCl (2×), saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo to afford the title compound (2.6 g, 94%): 1H NMR (CDCl3 400 MHz) δ 7.74 (dd, J=8.8, 2.2 Hz, 2H), 7.55 (dd, J=8.8, 2.2 Hz, 2H), 7.07 (m, 1H), 6.46 (m, 1H), 4.99 (dd, J=12.4, 2.9 Hz, 1H), 4.34 (dd, J=12.4, 2.2 Hz, 1H), 4.32 (s, 1H), 2.99 (t, J=6.6 Hz, 1H), 2.47 (t, J=7.3 Hz, 2H), 1.76 (m, 1H), 1.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@H:15]2[CH3:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@H:15]2[CH3:20])[N:3]=1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(CN1CCC(C(C)(C)O)CC1)n2C
Reaction time: 17 h
Yield: 92.1 %

Procedure:
A mixture of 2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde (279 mg, 0.94 mmol), 2-piperidin-4-ylpropan-2-ol (149 mg, 1.04 mmol) and 4 Å powdered molecular sieves (700 mg) in DCE (15 mL) was stirred for 5.5 h before the addition of sodium triacetoxyborohydride (400 mg, 1.89 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite®, washing with MeOH. The resulting filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording the title compound as a pale yellow solid (366 mg, 92%). LCMS (method H): RT 2.11 min [M+H]+ 423.4
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([N:12]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[N:27][O:28][CH3:29])[CH3:26])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])C=O)[N:5]=1>CO>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([NH:12][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[N:27][O:28][CH3:29])[CH3:26])[C:16]=2[C:17]([O:19][CH3:20])=[O:18])[N:5]=1
Reactant: CON=C(C)c1cccc(N(C=O)c2nc(OC)cc(OC)n2)c1C(=O)OC
Agent: Cl
Solvent: CO
Product: CON=C(C)c1cccc(Nc2nc(OC)cc(OC)n2)c1C(=O)OC
Temperature: 0 °C
Yield: 70 %

Procedure:
1 ml of concentrated hydrochloric acid was added to a solution of 1.34 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)-N-formylamino]-6-[1-(N-methoxyimino)ethyl]benzoate in 50 ml of methanol, and the mixture was allowed to stand at room temperature for one night. The reaction liquor was poured into an ice water, and was extracted with ethyl acetate. The organic layer thus formed was washed with sodium hydrogencarbonate aqueous solution and water in sequence, and was dried and concentrated. The residue thus obtained was purified by column chromatography to obtain 0.87 g of the aimed compound (melting point=82° to 84° C.) at a yield of 70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:7]1[C:2]([F:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Cl)cnc21
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 10.258 mmol) was placed in THF (15 mL) at −78° C. s-BuLi (16.12 mL, 22.57 mmol) was then added dropwise and stirred for 30 minutes. Hexachloroethane (6.07 g, 25.6 mmol) in THF (10 mL) was then added rapidly, and the reaction was stirred for an additional 30 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted into hexanes. The combined organic fractions were dried, filtered and concentrated to give the crude product that was purified by column chromatography (hexanes) to give 5-chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.1 g, 62% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)=[CH:18][CH:17]=2)[C:11]=1[OH:12])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[CH:14][C:15]=2[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)=[CH:20][CH:21]=2)[C:11]=1[OH:12])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccc5c(c4)OCO5)cc3)cnn2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2c(-c3ccc(Cc4ccc5c(c4)OCO5)cc3)cnn2c1O
Yield: 89.3 %

Procedure:
To a solution of 6-ethoxycarbonyl-7-hydroxy-3-[4-(3,4 -methylenedioxyphenylmethyl)phenyl]pyrazolo[1,5-a]pyrimidine (1.2 g) in ethanol (60 ml) was added 5N sodium hydroxide solution (3.0 ml), and the mixture was heated and refluxed for 20 hours. The solvent was distilled away under reduced pressure, and thereto was added water (100 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with water to give the title compound (1.0 g, 89.3%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10](C)=[C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:8]=[C:7]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[N:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:9]1[N:8]=[C:7]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COC(=O)c1nc(-c2cncc(C(F)(F)F)c2)nc(NCc2ccc(F)cc2F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(NCc2ccc(F)cc2F)nc(-c2cncc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.44 %

Procedure:
A solution of methyl 6-(2,4-Difluoro-benzylamino)-2-(5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxylic acid methyl ester (1 g, 0.0023 mol) in THF (10 ml), MeOH (10 ml) and H2O (10 ml) was added LiOH (0.198 g, 0.0047 mol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuum, reaction mass was diluted with water and neutralized with 5% citric acid solution. The obtained precipitate was filtered and washed with water, dried well under vacuum to get the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:13](O)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.C(N(CC)CC)C.[NH4+].[OH-]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:13]([NH2:25])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 103.9 %

Procedure:
A mixture of 1,3-dibenzylpyrrolidine-3-carboxylic acid (Example A28, 4.0 g, 13.5 mmol), 1,1′-carbonyldiimidazole (2.42 g, 14.9 mmol), and triethylamine (2.08 mL, 14.9 mmol) in tetrahydrofuran (100 mL) is heated at reflux for 1.5 hours. The solution is cooled, poured into NH4OH (300 mL), and stirred for 18 hours. The mixture is extracted with chloroform, the organic layer is washed with water, dried, and concentrated to afford 4.13 g of the title compound as an oil; MS El+: m/z 295 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: Nc1ccc(F)cc1NCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N2-Benzyl-4-fluoro-benzene-1,2-diamine (1.2 g, 5.55 mmol) was dissolved in DCM (20 mL) and (S)-2-tert-butoxycarbonylaminopropionic acid (1.14 g, 6.0 mmol) and HOAt (0.82 g, 6.0 mmol) added. The reaction mixture was cooled to 0° C. and N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (1.15 g, 6.0 mmol) added. The resultant dark brown mixture was stirred at 0° C. for 1 h. The mixture was allowed to reach RT and was diluted with DCM (20 mL) and washed with 10% aqueous citric acid. The organic fraction was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a dark yellow gum, which solidified on standing (1.7 g, 79%). LCMS (Method B): RT 3.67 min [M+H]+ 388.1
Reaction SMILES: [F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH2:12][C:13]([OH:15])=[O:14])([CH3:11])[CH2:8][CH2:7]2.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:14][C:13](=[O:15])[CH2:12][C:9]1([CH3:11])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:16][CH3:17])[C:2]=2[F:1])[CH2:7][CH2:8]1
Reactant: CO
Reactant: COc1ccc2c(c1F)C(C)(CC(=O)O)CC2
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(C)CCc2ccc(OC)c(F)c21
Reaction time: 4 h

Procedure:
The racemic carboxylic acid 38.4 (180 mg, 0.77 mmol) was dissolved in MeOH (40 mL) and a catalytic amount of concentrated sulfuric acid was added. The solution was heated to reflux and stirred for 4 hours. The reaction was concentrated under reduced pressure and diluted with EtOAc, washed with water, and washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate to give the racemic (7-fluoro-6-methoxy-1-methyl-indan-1-yl)-acetic acid methyl ester (194 mg, 0.77 mmol). The racemic methyl ester was subsequently dissolved in dichloroethane (8.0 mL) and cooled to 0° C. To the solution was added ethanethiol (0.17 mL, 2.4 mmol) followed by aluminum chloride (310 mg, 2.3 mmol). The reaction mixture was then warmed to room temperature and stirred for one hour. The reaction was diluted with DCM (300 mL) and washed with saturated sodium bicarbonate solution (200 mL). The aqueous layer was extracted with DCM (3×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was then passed through a plug of silica using an EtOAc:DCM mixture to give racemic 7-fluoro-6-hydroxy-1-methyl-indan-1-yl)-acetic acid methyl ester (170 mg, 93%). The racemic material was then purified by chiral HPLC (column: AD; solvent: 5% IPA/hexane) to yield 38.5 (64 mg, 38%) (retention time 30 minutes) and 38.6 (61 mg, 36%) (retention time 55 minutes). One of either 38.5 or 38.6 has the R stereochemistry at the β carbon and the other has the S stereochemistry at the β carbon. MS ESI (pos.) m/e: 239.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.75-6.87 (m, 2H), 5.20 (br. s., 1H), 3.64 (s, 3H), 2.87 (t, J=7.2 Hz, 2H), 2.66-2.84 (m, 2H), 2.33 (dt, J=12.9 Hz, 7.4 Hz, 1H), 1.99 (dt, J=13.0 Hz, 7.4 Hz, 1H), 1.46 (s, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH3:5].[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7].N1C=CC=CC=1>CCOCC>[C:6]([O:9][CH:3]([CH2:4][CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC(CC)OC(C)=O
Temperature: 0 °C

Procedure:
The above pentene derivative (9.0 g, 25 mmols) and acetic anhydride (3.0 g, 30 mmols) are dissolved in ether (200 ml), followed by dropwise adding pyridine (5 ml), while stirring the solution under ice cooling, stirring the reaction liquid under ice cooling for one hour, elevating the temperature up to room temperature, stirring for 3 hours, pouring the reaction mixture into ice water after completion of the reaction, extracting with toluene (150 ml), washing the organic layer with water, drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 5-(4-(4-propylphenyl)phenyl)cyclohexyl)-3-acetyloxy-1-pentene pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH2:17]Cl.C(N1C2C(=CC=C(C(O)=O)C=2)C=C1)C1C=CC=CC=1>>[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1cccc(C)c1CCl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C(O)c1ccc2ccn(Cc3ccccc3)c2c1
Product: COC(=O)c1ccc2ccn(Cc3c(C)cccc3C)c2c1
Yield: 88.4 %

Procedure:
The titled compound (7.4 g) as a white solid was prepared from methyl indole-6-carboxylate (5.0 g) and 2,6-dimethylbenzyl chloride (5.3 g) according to the method of the process (1) of Example 1.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl[CH:11]([C:17](=[O:19])[CH3:18])[CH:12](OC)OC.C([O-])(=O)C.[Na+]>O1CCOCC1>[C:17]([C:11]1[N:8]=[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][CH:12]=1)(=[O:19])[CH3:18]
Reactant: COC(OC)C(Cl)C(C)=O
Reactant: CCCCCCC(=N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCc1nc(C(C)=O)c[nH]1
Reaction time: 8 h
Yield: 42 %

Procedure:
Repeating the above procedure with 0.20 mole of heptanamidine, 0.15 mole 2-chloro-1,1-dimethoxy-3-butanone, 0.35 mole sodium acetate in 400 ml dioxane by refluxing for six hours, allowing to stand overnight at room temperature and work-up as above, affords a 42% yield of pure product, M.P. 104°-106° C. and 26% of impure product. For the pure sample: 1H-NMR (CDCl3) ppm (delta): 0.85 (t, 3H), 1.28 (m, 7H), 1.75 (m, 2H), 2.52 (s, 3H), 2.83 (t, 2H), 7.72 (s, 1H).