Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(OP(Cl)(OCC)=O)C.[CH:47](=O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([S:34](/[CH:37]=[CH:47]/[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:35])=[O:36])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(/C=C/c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a solution of LDA [8.5 mmol ; prepared by slow addition of n-butyl lithium (3.5 ml, 8.5 mmol, 2.5 M in hexane) to a solution of diisopropylamine (860 mg, 8.5 mmol) in dry THF (5 ml) at −78° C.] at −78° C. was added a solution of 1-(4-fluorophenyl)4-(methanesulfonyl)piperazine (1 g, 3.87 mmol) in THF (25 ml) dropwise. The mixture was stirred at −78° C. for 1 hour and a solution of diethylchlorophosphate (670 mg; 3.87 mmol) in THF (3 ml) was added. The mixture was stirred at −78° C. for 1 hour and benzaldehyde (450 mg; 4.24 mmol) in THF (3 ml) was added. The mixture was gently warmed to room temperature and stirred for 18 hours. The mixture was washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over MgSO4. Purification of the residue on silica (eluant: dichloromethane) afforded 1-(4-fluorophenyl)4(trans-β-styrenesulfonyl)piperazine as a white powder (621 mg, 46%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:22][CH:21]=1>CN1C(=O)CCC1>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)CCc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: NC(=O)CCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.060 g, 0.20 mmol) and 3-(4-aminophenyl)propanamide (0.066 g, 0.40 mmol) in NMP (3 mL) was microwaved for 3 h at 120° C., then at 140° C. for 2.5 h. After this time, the mixture was purified by silica gel chromatography eluting first with ethyl acetate and hexanes followed by methylene chloride and methanol. The solids were further purified by preparative HPLC to afford the title compound (0.042 g, 54%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.09 (br s, 1H), 9.82 (s, 1H), 7.90-7.89 (m, 1H), 7.71-7.58 (m, 3H), 7.33-7.27 (m, 5H), 6.98 (s, 1H), 6.77 (br s, 1H), 3.18-3.15 (m, 2H), 2.93-2.80 (m, 4H), 2.40-2.34 (m, 2H), 2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C(O)C>[OH:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:8]=1
Reactant: CC(=O)CCCCc1ccc(S(N)(=O)=O)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCCCc1ccc(S(N)(=O)=O)s1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
5-(5-oxohexyl)thiophene-2-sulfonamide (1.7 g) was dissolved in ethanol and 0.2 grams of sodium borohydride added. After 1 hour of stirring the reaction mixture was made acidic with 1N hydrochloric acid then concentrated under vacuum. This residue was treated with 1N hydrochloric acid to insure that no borate esters were present. The product was then extracted into ether, dried over sodium sulfate and concentrated under vacuum to give 1.3 grams of an oil plus solid mixture. This was chromatographed twice using 230-400 mesh gel and eluting with 0-10% methanol in chloroform providing 0.6 g of product which was recrystallized from water. m.p. 75°-76° C. N.M.R. (CDCl3)δ1.16 (d, 3H), 1.43 (m, 5H), 1.64 (m, 2H), 2.80 (t, 2H), 3.76 (m, 1H), 5.04 (bs, 2H), 6.69 (d, 1H), 7.42 (d, 1H), Analysis calculated for C10H 17 NO3S2 : C, 45.60%; N, 5.32%; H, 6.51% and found: C, 45.41%; N, 5.53%; H, 6.63%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][OH:25])[C:21]3[C:26]([O:29][CH3:30])=[N:27][NH:28][C:20]=3[CH:19]=2)=[O:16])[C:10]([OH:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:14][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][OH:25])[C:21]3[C:26]([O:29][CH3:30])=[N:27][NH:28][C:20]=3[CH:19]=2)=[O:16])[C:10]([OH:13])([CH3:11])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1n[nH]c2cc(NC(=O)NC(c3ccc(Cl)c(Cl)c3)C(C)(C)O)nc(CO)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1n[nH]c2cc(NC(=O)N[C@@H](c3ccc(Cl)c(Cl)c3)C(C)(C)O)nc(CO)c12
Reaction time: 0.1 h
Yield: 83 %

Procedure:
The enantiomers of 1-(1-(3,4-dichlorophenyl)-2-hydroxy-2-methylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea, TFA (15 mg, 0.033 mmol) were separated by SFC (Berger Multigram II, Column: Chiralcel OJ-H, 2.1×25 cm, 5 uM, UV wavelength: 220 nM, mobile phase: 85%/15% Methanol+0.25% dimethyl ethylamine/CO2(l), flow rate: 70 mL/Min, 10 min run time). Elution was observed at 5.8 min. The fractions were collected and the solvent evaporated in vacuo to afford (S)-1-(1-(3,4-dichlorophenyl)-2-hydroxy-2-methylpropyl)-3-(4-(hydroxymethyl)-3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (107, 6.2 mg, 0.014 mmol, 83.0% yield). MS: [M+H]+ m/z 454. 1H NMR (600 MHz, DMSO): 7.51-7.55 (m, 2H); 7.31 (dd, J=8.3, 2.0 Hz, 1H); 7.04 (s, 1H); 4.77 (s, 2H); 4.59 (d, J=8.6 Hz, 1H); 3.94 (s, 3H); 1.16 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:14]([N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:27][CH2:26][C:5]1=2)#[CH:15]
Reactant: Cc1ccc2c(c1)c1c(n2C#C[Si](C(C)C)(C(C)C)C(C)C)CCN(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 177.6 %

Procedure:
To a cooled solution of 2,8-dimethyl-5-((triisopropylsilyl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (10 g, 0.0236 mol) in THF (100 mL) was added tetrabutylammonium fluoride solution (1.0M in THF, 49 mL, 0.0526 mol) at 0° C. over 15 min. The reaction mixture was stirred for 1 h at 0° C., and the reaction monitored by TLC. After completion of reaction, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a brown colored oil (9.4 g).
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH:19]=[CH:18][C:17]2=[O:24]>>[O:24]=[C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:4]3[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=3)[CH:15]=2)[O:20][CH:19]=[CH:18]1
Reactant: O=c1ccoc2ccc(Br)cc12
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc3occc(=O)c3c2)cc1

Procedure:
The title compound was prepared as described in EXAMPLE 4A using 4-boronobenzoic acid in place of 4-(methoxycarbonyl)phenylboronic acid and 6-bromo-4H-chromen-4-one in place of 1-bromo-3-iodobenzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][CH3:13])=[CH:6][C:5]=1[OH:15].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:24][C:20]3[C:21]([C:11]=2[CH2:12][CH3:13])=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=3[F:26])=[CH:6][C:5]=1[OH:15]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCCC(=O)c1ccc(C(=O)OC)c(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCc1c(-c2ccc(C(=O)OC)c(O)c2)[nH]c2c(F)c(Cl)ccc12
Temperature: 120 °C

Procedure:
A mixture of 4-butyryl-2-hydroxy-benzoic acid methyl ester (60 mg, 0.27 mmol), (3-chloro-2-fluoro-phenyl)-hydrazine (Apollo Scientific, Ltd., 54 mg, 0.27 mmol), and zinc chloride (110 mg, 0.8 mmol) in acetic acid (2 mL) is purged with nitrogen for 5 minutes and then heated in a sealed tube at 120° C. for 2 hours. The mixture is cooled to room temperature and diluted with ethyl acetate. The resulting mixture is sequentially washed with saturated aqueous Na2CO3 and saturated aqueous NaCl, and finally dried over sodium sulfate. After concentration, the crude product is purified via silica gel flash column chromatography (10% ethyl acetate in hexanes) to afford 4-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester as a light yellow solid: ESMS m/z 348.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH2:17][CH2:18][CH2:19][C:20](OC)=[O:21]>>[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH2:17][CH2:18][CH2:19][C:20]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:9])([CH3:8])[CH3:1])=[O:21]
Reactant: COC(=O)CCCC1CC2C=CC1C2
Reactant: CC(C)(O)CCCCO
Product: CC(C)(O)CCCCOC(=O)CCCC1CC2C=CC1C2
Yield: 92 %

Procedure:
By following the procedure of Synthesis Example 2 except that 5-methyl-1,5-hexanediol was used instead of 4-methyl-1,4-pentanediol and methyl 4-(5-norbornen-2-yl)butyrate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 5-hydroxy-5-methylhexyl 4-(5-norbornen-2-yl)butyrate. Yield 92%.
Reaction SMILES: CSCCC#N.C1SC(NC(N)=N)=NC=1CS[CH2:18][CH2:19][C:20]([NH:22][S:23]([NH2:26])(=[O:25])=[O:24])=[NH:21]>>[S:23]([NH:22][C:20](=[NH:21])[CH:19]=[CH2:18])(=[O:25])(=[O:24])[NH2:26]
Reactant: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Agent: CSCCC#N
Product: C=CC(=N)NS(N)(=O)=O

Procedure:
N-sulfamyl-acrylamidine was prepared by a four-step procedure from 3-(methylthio)-propionitrile, with an extremely low (5.5%) yield in several days. The products of the subsequent steps, including famotidine, were isolated by column chromatography.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH3:28])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[C:1]([NH:5][C:6]([C:17]1[N:18]([CH3:28])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)N=C=O
Product: Cn1c(C(=O)NC(C)(C)C)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl

Procedure:
Using essentially the same procedure as Example 33, but using t-butyl isocyanate (0.040 mL, 0.30 mmol), 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20](=O)([O:23]C)[O:21][CH3:22].[Cl-].[NH4+]>C1COCC1>[C:8]([C:6]1[N:7]=[C:2]([CH2:1][C:20]([O:21][CH3:22])=[O:23])[CH:3]=[CH:4][CH:5]=1)#[N:9]
Reactant: Cc1cccc(C#N)n1
Reactant: COC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(C#N)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methylpicolinonitrile (2 g, 16.9 mmol) in THF (20 ml) was added slowly LiHMDS (17 ml, 1M in THF) at −78° C. under N2. Then the reaction mixture was stirred for 1 h at −78° C. and then dimethyl carbonate (1.52 g, 16.9 mmol) was added at −78° C. The mixture was stirred for 30 mins at −78° C. and allowed to 0° C. for 30 mins. Saturated ammonium chloride was added to neutralize to adjust to PH=7-8, the mixture was extracted by ethyl acetate (100 ml*3), the organic layer was dried by sodium sulfate, filtered, concentrated under vacuo to give the residue. The residue was purified by a standard method to give the desired product.
Reaction SMILES: [CH3:1][C:2]([C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][N:27]=[CH:28][C:21]=23)[S:17][C:18]=1[CH3:19])([CH3:13])[CH2:3][NH:4]C(=O)C1C=CC=CC=1.[OH-].[Na+]>CCO>[CH3:13][C:2]([C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][N:27]=[CH:28][C:21]=23)[S:17][C:18]=1[CH3:19])([CH3:1])[CH2:3][NH2:4]
Reactant: Cc1sc(-c2ccnc3[nH]ncc23)nc1C(C)(C)CNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(-c2ccnc3[nH]ncc23)nc1C(C)(C)CN
Temperature: 170 °C

Procedure:
N-[2-methyl-2-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]propyl]benzamide (55 mg, 0.1405 mmol) was dissolved in EtOH (1 mL) and treated with 5M NaOH (2.5 mL). The reaction was heated at 170° C. in the microwave for 500 minutes. The mixture was extracted with EtOAc followed by DCM and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (70:9:1, DCM/MeOH/NH4OH) to give the required product as a pale lemon solid (18.9 mg, 47% Yield). 1H NMR (DMSO, 400 MHz) δ 1.40 (6H, s), 2.61 (3H, s), 2.88 (2H, s), 7.51 (1H, s), 8.56 (2H, m); MS (ES+) 288.00
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]#[N:16])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.Cl.C(N(CC)CC)C.[N-:29]=[N+:30]=[N-:31].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[NH:31][N:30]=[N:29][N:16]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: N#CCN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Clc1ccc(OC2CC3CCC(C2)N3Cc2nnn[nH]2)cc1Cl
Temperature: 61 °C
Reaction time: 120 h

Procedure:
To 1 g of [3-(3,4-dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-acetonitrile in 25 ml anhydrous toluene was added 0.7 g of triethylamin hydrochloride and 0.3 g sodium azide. The reaction mixture was stirred at 60-62° C. for 5 days, the product precipitated from the mixture and was isolated by filtration. Yield 0.27 g (24%) Mp. 233-235° C. (sublimation).
Reaction SMILES: [CH:1]([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C@@H:26]([CH2:35][CH3:36])[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])[C:16](=[O:37])[C@H:15]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1.IC.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[C@@H:18]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:17]([C@@H:26]([CH2:35][CH3:36])[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][S:29]3(=[O:34])=[O:33])[C:16](=[O:37])[C@@:15]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[N:40]=3)([CH3:1])[CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: [Li]C(C)CC
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@](C)(Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
sec-Butyllithium (1.4 M in cyclohexane, 0.59 ml, 0.824 mmol) was added to a solution of (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one (Example 420, Step C, 0.484 g, 0.785 mmol) in THF (3.92 ml) at −78° C. After 15 minutes iodomethane (0.098 ml, 1.57 mmol) was added and the reaction was allowed to warm to room temperature. The reaction contents were poured into saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (10% step gradient elution 30 to 90% EtOAc in hexanes) afforded the title compound as the first eluting diastereomer.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:16]
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Reactant: CNC
Product: CCOC(=O)N1CCC(O)(CN(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate are added dropwise to 30 ml of dimethylamine solution (40% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and distilled.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)OC(C)(C)C)[N:10]=2)[N:7]=1.Cl.C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Nc1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a suspension of tert-butyl (6-iodoimidazo[1,2-b]pyridazin-2-yl)carbamate (10.2 g, 28.3 mmol) in ethyl acetate (50 mL) was added 4N hydrochloric acid/ethyl acetate (75 mL), and the mixture was stirred at room temperature for 4 hr. Diethyl ether (200 mL) was added to the reaction mixture, and the precipitate was filtrated. After washing with saturated aqueous sodium hydrogencarbonate solution, the filtrate was washed with water, acetonitrile and diethyl ether to give the title compound (4.9 g, 67%) as a green powder.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]1=[O:13])[CH3:2].O.[OH-].[Li+].Cl>O.CO>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][C:4]1=[O:13])[CH3:2]
Reactant: CCn1cc(C(=O)OC)ccc1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Methyl 1-ethyl-2-oxo-1,2-dihydropyridine-5-carboxylate (375 mg, 2.07 mmol) obtained in Step 4 was dissolved in a mixed solvent (1:1) (20 mL) of water and methanol, and lithium hydroxide monohydrate (191 mg, 4.55 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized with 3 mol/L hydrochloric acid added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound u (224 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[C:4]([F:20])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 34.8 %

Procedure:
2-(4-Chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3 g) was dissolved in dimethylformamide (100 ml), and anhydrous potassium carbonate (0.8 g) was added tereto. To the resultant mixture was added methyl bromoacetate (1.8 g), and the mixture was heated at 70°-80° C. for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ether, and the extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to give 1.3 g of 2-(4-chloro-2-fluoro-5-methoxycarbonylmethoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (Compound No. 1). M.P., 98°-99.5° C.
Reaction SMILES: [I-].[Na+].[Li][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[I-].S([O-])(=O)(=O)C>C1COCC1>[CH:14]1[C:15]2[C:16](=[O:18])[C:17]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: [Li]c1cccc2c1C(=O)c1ccccc1C2
Agent: CS(=O)(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2Cc2ccccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
10,10-Bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (I) Two solutions are prepared. For one, 1.0 M lithium t-butoxide in THF (1.00 L, 1.00 mol) was added to a solution of anthrone (70.0 g, 0.36 mol) in THF (0.70 L) at 15-30° C. to form lithio anthrone. The second solution was prepared by mixing sodium iodide (45.0 g, 0.30 mol) VI-i (150.0 g, 0.73 mol) and THF (1.60 L) at 40° C. for 3 h to form a mixture of VI-i/VII-i. The lithio anthrone solution was added dropwise over 100 min at 40-50° C. to the iodide/mesylate solution. The reaction was aged for 1 h (the HPLC peak area of VII-i was <1%). The solution was washed with saturated aqueous brine (2×0.90 L). Volatiles were removed in vacuo and the residue was diluted with toluene (1.3 L). The solution was heated to 100° C., cooled to 90° C. and stirred with basic alumina (120 g) for 30 min. The solution was filtered through a Celite pad, concentrated by atmospheric distillation to 500 mL and cooled to 25° C. to crystallize I. Further crystallization was induced by the dropwise addition of n-heptane (0.60 L) followed by cooling to 0° C. for 2 h. The crystals were collected by filtration, washed with n-heptane (0.2 L) and dried at 60° C. in vacuo to yield 121 g of I (75% yield from anthrone, 92 HPLC wt % purity versus a reference standard).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:20]=1[C:21](O)=[O:22])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:21]([C:20]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=[CH:27][C:19]=1[O:18][CH:15]([CH3:17])[CH3:16])=[O:22])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (CA [1745-07-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1I.[Br-].[CH:17]1([Zn+])[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>>[CH:17]1([C:5]2[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [Zn+]C1CCCC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(C(F)(F)F)cc1C1CCCC1

Procedure:
In analogy to the procedure described for the synthesis of example B.10, the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid methyl ester and cyclopentyl zinc bromide followed by saponification with sodium hydroxide. MS (m/e): 257.0 (M−H).