Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[C:15]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:14]=3[CH:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:5][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17][C:15]=3[C:16]=2[CH:8]=[C:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc2c(ccc3c4ccccc4sc23)[nH]1
Product: CCOC(=O)c1cc2c3sc4ccccc4c3ccc2n1C

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-[1]benzothieno[2,3-e]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a nearly quantitative yield of crude ethyl 3-methyl-3H-[1]benzothieno[2,3-e]indole-2-carboxylate. This material was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a crude mixture of aldehydes which was hydrolyzed and decarboxylated without purification using the procedure outlined in Example 15B to give a 19.0% yield of 3-methyl-3H-[1]benzothieno[2,3-e]indole-1-carbaldehyde.0.25 H2O, mp 223.5°-224°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N+:4]([O-:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:11][O-:12].[Na+].CO>>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N+:4]([O-:9])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)ccc(C)[n+]1[O-]

Procedure:
step b—A solution of 357a (0.5 g) and 0.5 M NaOMe/MeOH (4.9 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue loaded on a SiO2 column and eluted with 5% MeOH/DCM to afford 3-bromo-2-methoxy-6-methyl-pyridine 1-oxide (357b).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:17])[C@H:14]([NH2:16])[CH3:15].C(Cl)CCl.[C:22]([NH:32][C@H:33]([C:36](O)=[O:37])[CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[C@H:14]([NH:16][C:34](=[O:35])[C@@H:33]([NH:32][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:36][OH:37])[CH3:15]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
Diisopropylethylamine (375 mL) was added dropwise to a cooled mixture of (R)-2-amino-propionic acid methyl ester hydrochloride (100 g, 0.716 mol), EDC (165 g, 0.86 mol), carbobenzyloxy-L-serine (171.4 g, 0.716 mol) and DCM (3.6 L). The resulting mixture was stirred under nitrogen at ambient temperature for 16 h. After removing solvent in vacuo at 40° C., the residue was diluted with saturated sodium carbonate (1 L), water (1 L) and extracted with EtOAc (2 L, 2×1 L). The combined organic phases were washed with 2 M hydrochloric acid (1 L), saturated brine solution (1 L), dried over magnesium sulfate and concentrated in vacuo at 40° C., to give the title compound (172 g) as a colourless solid. 1H NMR (Me-d3-OD): 7.44-7.28 (6H, m), 5.13 (2H, s), 4.46 (1H, d), 4.43 (1H, d), 4.25 (1H, t), 3.82-3.68 (5H, m), 1.39 (3H, d).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[O:30]=[C:29]([C:28]1[CH:32]=[CH:33][C:25]([CH3:24])=[CH:26][CH:27]=1)[CH:7]([C:3]1[CH:2]=[C:1]([CH3:13])[CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)Cc1cccc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(C)cc1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
To a cooled (−78° C.) solution of ethyl 2-m-tolylacetate (1.697 g, 9.52 mmol) in THF (10.58 mL) was added LiHMDS (9.52 mL, 9.52 mmol). The reaction was stirred for 15 minutes and 4-methylbenzoyl chloride (1.546 g, 10 mmol) in THF (21.16 mL) was slowly added. The reaction was allowed to warm to room temperature over 2 h. The reaction was quenched with AcOH, diluted with water and extracted with EtOAc three times. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow oil (2.213 g). 1H NMR (400 M Hz, CDCl3) δ ppm 1.24 (t, J=7.07 Hz, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 4.15-4.28 (m, 2H), 5.54 (s, 1H), 7.10 (d, J=7.07 Hz, 1H), 7.16-7.25 (m, 5H), 7.85 (d, J=8.08 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([N+:21]([O-:23])=[O:22])=[CH:16][CH:17]=3)[CH:12]2[CH2:24][C:25]([OH:27])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:60]([NH:62][CH2:63][CH3:64])[CH3:61].C(N(C(C)C)CC)(C)C.[Na+].[Cl-]>CN(C=O)C>[CH2:60]([N:62]([CH2:63][CH3:64])[C:25](=[O:27])[CH2:24][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[CH3:61]
Reactant: O=C(O)CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)OCc1ccccc1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CC1c2cc([N+](=O)[O-])ccc2CCN1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(phenylmethoxy)carbonyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-1-acetic acid (5.0 g, 13.5 mmols), HOBT (1.8 g, 13.5 mmols) and TBTU (4.3 g, 13.5 mmols) in DMF (50 ml) was added diethylamine (13.5 mmols). To this was added slowly diisopropylethylamine (7.0 ml) and the reaction was then stirred for 48 h. The reaction was then poured into saturated NaCl and the aqueous phase then extracted with ethyl acetate (3×100 ml). The solvent was evaporated to leave a crude oil which was used as such.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH:35]1([NH2:38])[CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:38][CH:35]3[CH2:37][CH2:36]3)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)NC3CC3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for min (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), cyclopropylamine (13 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 63 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (27 mg, 82% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][C:22]1([CH3:28])[CH2:24][CH:23]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH:8][C:25]([CH:23]1[CH2:24][C:22]1([CH3:28])[CH3:21])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC1C(=O)Cl
Reactant: CCCCC(N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(NC(=O)C1CC1(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Patent No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5N HCl, then with 2×200 ml of 0.5N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52°→65°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>CN(C=O)C.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>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a flask charged with Pd(PPh3)4 (46 mg, 0.040 mmol) under nitrogen was added a solution of 6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 mL). The system was purged with nitrogen gas three times and then tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42 mmol) was added. The temperature was increased to 100° C. and stirred for 2 h. Then the reaction mixture was cooled to rt, 3N HCl was added and the mixture was stirred for additional 4 h. Water was added and the product was then extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 120 mg (90%) of the title compound. LCMS (method B): [MH]+=335, tR=2.41 min.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])(=O)C.[OH-].[NH4+]>O>[SH:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:8]
Reactant: CC(=O)SCCC(=O)NC1(C(=O)O)CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(CCS)NC1(C(=O)O)CCCC1

Procedure:
The product of Example 3 (1.04 g.) is treated for 1 hour, under an argon blanket, with a solution of 2.4 ml. of water and 1.6 ml. of concentrated ammonium hydroxide solution. The reaction mixture is diluted with water, extracted twice with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid and extracted into ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and concentrated in vacuo. The product, 1-[(3-mercaptopropanoyl)amino]cyclopentane carboxylic acid, is crystallized from ethyl acetate and recrystallized from acetonitrile, yield 343 mg., m.p. 175°-176°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 78.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloro-quinolin-8-ylamine (Intermediate 27) (380 mg, 2.13 mmol), 2-nitrobenzene-1-sulfonyl chloride (566 mg, 2.56 mmol), pyridine (0.34 ml, 4.26 mmol) and DCM (12 ml) gave the title compound (610 mg, 79%) after purification by column chromatography with n-hexane/DCM (1:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[CH:16])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.I[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(N)CCC.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>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:21][CH:22]=1
Reactant: C#CCCN1CCC(Cc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1ccc(C#CCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 11.7 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-1-(but-3-yn-1-yl)piperidine (318 mg, 1.21 mmol) and 4-iodoaniline (265 mg, 2.19 mmol) in 10 mL of butylamine is added 70 mg of Pd(PPh3)4. The resulting solution is allowed to reflux for 24 hr. The solvent is evaporated in vacuo and the residue is purified by flash chromatography giving the title product as a brown oil (50 mg, 12%): 1H NMR (CDCl3) 1.24 (m, 2 H), 1.44 (m, 1 H), 1.58 (m, 2 H), 1.96 ( m, 3 H), 2.15 (m, 2 H), 2.55 (m, 4 H), 2.89 (m, 2 H), 3.75 (bs, 2 H), 6.53 (d, J=6.0 Hz, 2 H), 7.05 (m, 2 H), 7.20 (m, 4 H).
Reaction SMILES: COCCOC[O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1.S(=O)(=O)(O)O.C(O)C>C1COCC1>[OH:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=2)=[CH:10][C:11]2[C:12]([CH3:20])([CH3:21])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCOCCOC)C(C)(C)CCC3(C)C)nc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
A mixture of ethyl 6-(3-methoxyethoxymethoxy5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)nicotinate (2.6 g, 5 mmol), concentrated sulphuric acid (535 μl), ethanol (75 ml) and THF (25 ml) is stirred for 3 days at room temperature. The reaction medium is extracted with ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum. The solid obtained is washed with ethyl ether. 2.01 g (93%) of the expected compound are obtained in the form of an orange-coloured powder. m.p.=138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].O>CN(C)C=O.C(Cl)Cl.CCOCC>[CH:30]([O:29][C:27](=[O:28])[CH2:26][N:13]1[C:12](=[O:16])[N:11]([CH3:17])[C:10](=[O:18])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]1=[O:15])([CH3:32])[CH3:31]
Reactant: Cn1c(=O)[nH]c(=O)n(-c2ccc(F)cc2Cl)c1=O
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2ccc(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 1-(2-chloro-4-fluorophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (40.9 g, 0.150 mol), potassium carbonate (31.1 g, 0.225 mol) and isopropyl bromoacetate (29.1 mL, 0.225 mol) in N,N-dimethylformamide is stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The organic extract is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and 0% to 10% ether in methylene chloride solutions gives the title product as a white solid (51.5 g, mp 127°-128° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:23]3[C:24]4[O:28][CH2:27][O:26][C:25]=4[CH:29]=[CH:30][C:22]=3[O:21][CH2:20][CH:16]3[CH2:17][CH2:18][CH2:19]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2c(OCC3CCC3)ccc3c2OCO3)OC1(C)C
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-cyclobutylmethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A30) the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:7]1([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[CH2:8]1)[CH2:6][CH:5]2O.[CH3:28][N:29]=[C:30]=[O:31].C(O)(=O)/C=C/C([O-])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:7]1([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[CH2:8]1)[CH2:6][CH:5]2[C:30](=[O:31])[NH:29][CH3:28]
Reactant: O=C(CCCN1CCC2(CC(O)c3cc(Cl)ccc32)C1)c1ccc(F)cc1
Reactant: CN=C=O
Agent: O=C([O-])/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1CC2(CCN(CCCC(=O)c3ccc(F)cc3)C2)c2ccc(Cl)cc21

Procedure:
4-(5-Chloro-3-hydroxyspiro[indan-1,3'-pyrrolidin]-1'-yl)-p-fluorobutyrophenone is reacted with methyl isocyanate in chloroform in a manner analogous to that described in Example 19. Reaction time 24 hours at the boil. The hydrogen fumarate of the title compound has a M.P. of 151°-153° (from ethanol/ether).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1CN(Cc2ccccc2)CC1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 15.58 g (82.3 mmol) sample of the ketone from step d was reduced to the alcohol by dissolving it in 32 mL of ethanol and adding the solution dropwise to a stirred suspension of sodium borohydride (3.11 g, 82.3 mmol) in 32 mL of ethanol at 0° C. The suspension was then stirred for 30 min at 0° C. and for 4 hours at room temperature. The solvent was then removed and the residue suspended in water. The product was extracted with methylene chloride and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under vacuum. The crude product was purified in a kugelrohr apparatus (160°-180° C. @ 1.0 Torr) to yield 1-benzyl-4-methyl-3-pyrrolidinol, MS M/Z 192 (M+H); NMR (CDCl3) d 1.04 (d, 3H, J=7.5 Hz), 1.90 (dd, 1H, J=7.5 Hz, J=9.0 Hz), 2.14 (m, 1H), 2.55 (dd, 1H, J=6.0 Hz, J=10.5 Hz), 2.82 (dd, 1H, J=3.0 Hz, J=10.5 Hz), 3.13 (dd, 1H, J=3.0 Hz, J=3.0 Hz), 3.82 (m, 2H), 3.95 (m, 1H), 7.33 (m, 5H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][N:15]([C@H:24]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][N:15]([C@H:24]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:14]1)=[O:11]
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
A solution of 1.29 mL (14.8 mmol) of oxalyl chloride in 15 mL of CH2Cl2 at −78° C. was treated with 2.10 mL (29.7 mmol) of DMSO maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 5 min. A solution of 2.33 g (5.9 mmol) of 2-(R)-(3-(R)-(hydroxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propionic acid, benzyl ester (from Step B) in 10 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 30 min. The mixture was treated with 10.3 mL (59.3 mmol) of DIEA maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 20 min and quenched with H2O. The mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O and the layers were separated. The aqueous layer was extracted with 250 mL of CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated. Flash chromatography on 100 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 2.30 g (97%) of the title compound: 1H NMR (300 MHz) δ 1.54-2.08 (m, 8H), 2.31 (m, 1H), 2.75 (t, J=8.6 Hz, 1H), 2.96 (m, 1H), 3.11-3.35 (m, 4H), 3.56 (q, J=7.9 Hz, 1H), 5.16 (s, 2H), 7.19-7.39 (m, 1OH), 9.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: C([O:8][C@@H:9]([C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH2:10]([C@H:9]([C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)[OH:8])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(c1ccccc1)[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Agent: [Pd]
Solvent: CC(=O)O
Product: O[C@H](Cc1ccccc1)[C@H]1COC2(CCCCC2)O1
Yield: 65.3 %

Procedure:
(iv)(a) A solution of 130 mg (0.35 mmol) of β(R)-benzyloxy-α(RS)-phenyl-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in 3 ml of acetic acid was hydrogenated over 10% palladium-on-carbon under a pressure of about 4.1 atmospheres for 2 days. The catalyst was removed by filtration and the filtrate was evaporated. The crude product was purified by flash chromatography on silica gel using 2% methanol in dichloromethane for the elution. There were obtained 60 mg of α(R)-benzyl-1,4-dioxaspiro-[4,5]decane-2(R)-methanol in the form of a colourless oil; MS: m/e 262 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: NCCCO
Reactant: N#Cc1ccc(Cl)cc1F
Product: NCc1ccc(Cl)cc1NCCCO

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 3-amino-propanol analogously to the preparation of Intermediate 113.1. colorless oil; ES-MS: M−=213.1; HPLC: AtRet=2.27 min.