Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[C@H:9]([O:11][CH3:12])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][NH:21][C:20]1[CH:22]=[CH:23][C:17]([Br:16])=[CH:18][CH:19]=1)[C@H:9]([O:11][CH3:12])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CO[C@H](C)[C@@H](CNc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 18.6 %

Procedure:
To a solution of ((1S,2R)-1-formyl-2-methoxy-propyl)-carbamic acid t-butyl ester (1.92 g, 8.8 mmol) and 4-bromoaniline (1.51 g, 8.8 mmol) in dichloroethane (50 mL) was added sodium triacetoxyborohydride (3.73 g, 17.6 mmol) portionwise. After the addition, the resulting mixture was stirred at rt for over night. The reaction mixture was quenched with saturated NaHCO3, and extracted with DCM (4×40 mL). The combined DCM was dried (Na2SO4) and concentrated. The residue was subjected to ISCO (120 g column, 0-40% EtOAc in hexane over 100 min.) to give the titled compound (610 mg). MS (MH+ 373 and 375).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:2]2[C:7]([S:8]([N:11]3[CH2:12][CH2:13][C:14]4([C:18](=[O:19])[N:17]([C:20]5[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=5)[CH2:16][CH2:15]4)[CH2:31][CH2:32]3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:35][CH2:34]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: NC1CC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1NC1CC1)CC2

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and cyclopropyl amine. Light yellow oil. MS (ESI): 511.2 (MH+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([OH:14])[C:10]([CH3:13])=[CH:11][CH:12]=1>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([OH:14])[C:10]([CH3:13])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(Cl)cc1O
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1O
Reaction time: 0.17 h
Yield: 2.4 %

Procedure:
To a solution of chlorosulfonic acid (3.69 g, 31.65 mmol) dissolved in 30 mL of dichloromethane was added 3-chloro-6-methylphenol (3.0 g, 21.1 mmol) dropwise. After 10 minutes, the reaction was quenched by pouring it into ice water. The reaction was extracted with dichloromethane, washed with brine, dried over MgSO4, filtered, and concentrated to give 120 mg (2.4%) of the title compound.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C@@H:16]([CH3:28])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[C@@H:16]([CH3:28])[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H]1CN(C(c2ccccc2)c2ccccc2)CCN1CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(C(c2ccccc2)c2ccccc2)CCN1CC(=O)O

Procedure:
A solution of (S)-tert-butyl 2-(4-benzhydryl-2-methylpiperazin-1-yl)acetate (340 mg, 894 μmol) in 3 mL of 1,4-dioxane and 1 mL of concentrated HCl solution (37%) was stirred at rt overnight. The solvent was evaporated to dryness and the residue was crashed out of ether to give (S)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid dihydrochloride as a white solid. MS (ESI, pos. ion) m/z: 325 (M+1).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>ClCCl>[Cl:18][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]=1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: ClC1=Nc2cccnc2Nc2ccccc21

Procedure:
A solution of 5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (18 g, 85.3 mmol) and PCl5 (20.5 g) in dichloromethane (650 mL) was stirred at reflux until the starting material was all consumed (use LC/MS to follow the reaction). The reaction mixture was concentrated in vacuo to half volume and the resulting solid was collected by filtration and washed with dichloromethane. The filtrate was further concentrated and a second crop was similarly obtained and combined. The 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine was obtained as a yellow solid (total 14 g, 71%). LCMS [M+H]: 230.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[N:7][C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:5]1)[CH:2]=[CH2:3].C([N:28]1[C:32]([C:33]2[CH:38]=[CH:37]C(OC)=CC=2)=NC(C2C=C(C=CC=2)C=O)=N1)C=C.N1CCCC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:72].CCO>C1COCC1.C(O)C>[ClH:72].[CH2:1]([N:4]1[C:8]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][N:28]3[CH2:32][CH2:33][CH2:38][CH2:37]3)[CH:10]=2)=[N:7][C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2)nc1-c1cccc(C=O)c1
Reactant: C=CCn1nc(-c2cccc(C=O)c2)nc1-c1ccc(OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCn1nc(-c2ccc(OC)cc2)nc1-c1cccc(CN2CCCC2)c1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
A solution of mixture of 3-[2-allyl-5-(4-methoxy-phenyl)-2H-[1,2,4]triazol-3-yl]-benzaldehyde and 3-[1-allyl-5-(4-methoxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (1:1) (60 mg, 0.19 mmol), pyrrolidine (19 μl, 5 0.23 mmol) and acetic acid (13 μl, 0.023 mmol) in THF (5 ml) was stirred for 15 min at r.t then sodium triacetoxyborohydride (59 mg, 0.28 mmol) was added in a single portion. This mixture was allowed to react at r.t. under argon until all the aldehyde had been consumed (ca. 1.5 hr). Saturated aqueous Na2CO3 solution was then added, stirred for 15 min and extracted twice with EtOAc (20 ml). The combined organic phase was dried with Na2SO4 filtered and the solvent evaporated under reduced pressure. The resulting isomeric mixture, obtained as an oil, was chromatographed over SiO2 (Merck 230-400 mesh) using CH2Cl2/(2M NH3 in MeOH) 97:3, to provide the separate regioisomers. The isolated regioisomer was taken up in ethanol and was directly converted to its hydrochloride salt with 1.45N HCl/EtOH at 4° C. Following solvent evaporation the resulting white foam was dried under high vacuum (0.05 mmHg) at 50° C. for 3 h to afford the title compound (25 mg, 0.06 mmol, 32.4%), MS: m/e=375.4 (M+H+). The regiochemistry of alkylation was established by 1H-NMR, nOe spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23]O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COC(=O)c1ccc(F)cc1O
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1OCCCNC(=O)OC(C)(C)C

Procedure:
Using a procedure equivalent to Example 1-F, methyl 4-fluoro-2-hydroxybenzoate and 3-(tert-butoxycarbonylamino)-propanol gave the ether product as a white solid (20.6 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:17]([OH:19])=[O:18])[NH:13]C(=O)C)([O-:3])=[O:2]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:17]([OH:19])=[O:18])[NH2:13])([O-:3])=[O:2]
Reactant: CC(=O)N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=S(=O)(O)O
Product: N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution of 13.6 g (47.9 mmol) of S-(o-nitrophenyl)-N-acetyl-D-cysteine was refluxed in 57 mL of 18M sulfuric acid (H2SO4) for 1 hour. The bright yellow solution was cooled to 0° C. and concentrated. Ammonium hydroxide (NH4OH) was added to adjust the pH=5.4. The resulting precipitate was filtered and dried to yield 11.6 g (100% ) of product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[CH3:16][Mg]I.CI.[Mg].[Cl-].[NH4+]>C1C=CC=CC=1.C(OCC)C>[C:10]1([C:4]2[C:5]([CH3:16])([CH3:9])[NH:6][C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Mg]I
Reactant: Cc1nc(=O)n(C)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CI
Product: CN1N=C(c2ccccc2)C(C)(C)NC1=O
Reaction time: 1 h

Procedure:
A hot solution of 2,5-dimethyl-6-phenyl-1,2,4-triazin-3(2H)-one (5 g) in benzene (60 ml) was added dropwise to a stirred solution of methylmagnesium iodide prepared from methyl iodide (17.5 g) and magnesium turnings (3 g) in diethyl ether (80 ml) at room temperature. The solution was refluxed under heating for 40 minutes and then allowed to stand for 1 hour at room temperature. The solution was treated with a saturated aqueous solution of ammonium chloride to decompose excess Grignard reagent. The organic layer was separated, dried over magnesium sulfate, treated with activated charcoal, and evaporated to dryness. The resultant solid was recrystallized from a mixture of diispropyl ether and chloroform to give 6-phenyl-2,5,5-trimethyl-4.5-dihydro-1,2,4-triazin-3(2H)-one (4.21 g), m.p. 128°~130° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[CH:16]=[O:17]>CN(P(N(C)C)(N(C)C)=O)C.O>[CH2:14]([C:10]1[C:9]([CH:16]=[O:17])=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:12]([CH3:13])[N:11]=1)[CH3:15]
Reactant: C1COCCN1
Reactant: CCc1nn(C)c(Cl)c1C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCc1nn(C)c(N2CCOCC2)c1C=O
Temperature: 90 °C
Yield: 82.5 %

Procedure:
Morpholine (35.15 g, 0.4 mol) and water (30 mL) were added under stirring at room temperature to a mixture of 5-chloro-3-ethyl-1-methyl-1H-pyrazole-4-carbaldehyde from Step 2 (35 g, 0.202 mol) in HMPA (30 mL). The reaction mixture was heated at 90° C. for 8 h, then diluted with water and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with water to obtain a weak alkaline media, dried over Na2SO4 and evaporated. The residue was purified by chromatography (hexane/ethyl acetate) on silica gel to afford 37.2 g (82.6%) of the title product. Satisfactory C,H,N-analysis was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C@@H:11]1[N:16]([CH3:17])[C:15](=O)[CH2:14][NH:13][C:12]1=O)([CH2:9][CH3:10])[CH3:8].N1CCNCC1>C1COCC1.C(OCC)C>[CH:7]([C@H:11]1[CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH3:17])([CH2:9][CH3:10])[CH3:8]
Reactant: CCC(C)[C@H]1C(=O)NCC(=O)N1C
Agent: C1CNCCN1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C)[C@H]1CNCCN1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
An oven-dried, nitrogen purged flask was charged with 124 mg LiAlH4 (3.26 mmol) and suspended in 2.0 mL anhydrous THF. Diketopiperazine 11 (200 mg, 1.09 mmol) was added dropwise as a solution in 7.0 mL anhydrous THF. The reaction was stirred at room temperature for 1.5 hours, followed by heating at 40° C. for 5 hours. The reaction was allowed to cool to room temperature, diluted with ca. 10 mL diethyl ether, quenched with sequential addition of 60 μL H2O, 120 μL 10% NaOH, 180 μL H2O, and the resulting aluminum salts filtered off. The organic solution was dried over MgSO4 and evaporated to dryness under reduced pressure to yield 140 mg (82% yield) of product piperazine as a slightly brown oil which was used immediately without further purification. MS (ESI-TOF) MH+ expected: 157.1699, found: 157.1703.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>ClCCl>[C:18](=[O:19])([O:20][CH3:21])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: COC(=O)Cl
Reactant: Cc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(Br)cc1C
Temperature: 25 °C
Yield: 86.2 %

Procedure:
4-Bromo-2-methyl-phenol (3.63 g, 19.41 mmol) was dissolved in dichloromethane (18 mL) and triethylamine (5.41 mL, 38.80 mmol), cooled to 0° C., then treated with methyl chloroformate (2.25 mL, 29.12 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts was dried over Na2SO4, filtered, and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (10% ethyl acetate/hexane) to yield 4-bromo-2-methylphenyl methyl carbonate (4.1 g, 86% yield) as a white solid. 1H NMR (400.0 MHz, DMSO-d6) δ 7.56 (d, J=2.1 Hz, 1H), 7.44 (dd, J=2.3, 8.6 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 3.84 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (2.2 mmol) in 15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine, is stirred at room temperature until a clear solution is obtained. 4,6-Dichloropyrimidine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at high temperature until formation of the desired compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2cccnc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and pyridine-3-boronic acid. The crude product was purified by preparative HPLC (Gilson) (5%, brown oil).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([SH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>CN(C)C=O>[OH:18][CH:7]1[C:8]2[C:13](=[CH:12][C:11]([S:15][CH2:27][C:28]([OH:30])=[O:29])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(SCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
(1-Hydroxy-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanylthio)acetic acid is prepared following substantially the same procedure described in Example 4, Step F, using the following substances: 2-cyclopentyl-2-methyl-5-mercapto-6,7-dichloro-1-indanol (4.5 g., 0.015 mole); potassium carbonate (3.6 g.); ethyl bromoacetate (3.1 ml.); and dimethylformamide (35 ml.); and hydrolyzing the resultant ester with aqueous sodium hydroxide in accordance with Example 4, Step F, there is obtained (1-hydroxy-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanylthio)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[NH:10]([CH2:14][CH2:15]O)[CH2:11][CH2:12]O>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:15][CH2:14][NH:10][CH2:11][CH2:12]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: OCCNCCO
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Product: Cc1ccc(N2CCNCC2)cc1Cl
Temperature: 240 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
To a mixture of 3-chloro-4-methylaniline (105.5 g, 0.745 mol) and diethanolamine (78.1 g, 0.745 mol) was added slowly with stirring and cooling, concentrated hydrochloric acid (c.a. 100 ml) to adjust the reaction mixture to pH 7. The reaction mixture was heated to remove water (66 ml), after standing for 18 h the mixture was heated to 240° C. for 6 h. Sodium hydroxide (5N, solution, 236 ml) was added and the product was extracted with chloroform (4×100 ml). The combined organic extracts were concentrated to give a red oil which was purified by distillation to give the title compound (107.0 g, 68%)
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C>>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[C:24]([CH3:25])[CH:23]=[CH:22][CH:21]=2)[N:15]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: Cc1cccc(C(N)=O)c1N
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Product: Cc1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 115 °C
Yield: 49.1 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.02 g, 4.8 mmol) and 2-amino-3-methyl-benzamide (0.6 g, 4.0 mmol) were combined with trimethylsilyl polyphosphate (8.0 mL) and the mixture was heated at 115° C. for 18 h with vigorous stirring. The mixture was allowed to cool to rt, then the mixture was partitioned between water (15 mL) and ethyl acetate (15 mL). The organic layer was separated and the aqueous layer (pH˜1) was extracted with ethyl acetate (30 mL×3). The combined organic layers were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:10 to 1:1 EtOAc/hexanes to afford 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-3H-quinazolin-4-one as an off-white solid (0.6 g, 29%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]([F:16])=[CH:14][C:13](/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[F:23])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:26]>>[F:23][C:11]1[CH:12]=[C:13](/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20])[CH:14]=[C:15]([F:16])[C:10]=1[O:9][C:8]1[CH:24]=[CH:25][C:5]([S:2](=[O:4])(=[O:3])[NH2:26])=[CH:6][CH:7]=1
Reactant: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)Cl)cc2)c(F)c1)C(=O)O
Reactant: N
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(N)(=O)=O)cc2)c(F)c1)C(=O)O

Procedure:
(E)-3-(4-(4-(chlorosulfonyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylic acid (Intermediate 51.2) was converted to intermediate 58.1 using procedures outlined in Example 58, with aqueous ammonia as the amine. The title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[Br:20]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)c(Br)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.3 %

Procedure:
2.50 g (11.9 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 75 ml of dioxane, 1.86 g (13.1 mmol) of N-bromosuccinimide was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with a mixed solution of chloroform and methanol. The extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetone=40:1) to give 170 mg (4.3%) of Compound 4.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[C:14]1([C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17])[OH:15]>C1(C)C=CC=CC=1>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:15][C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[OH:17])=[O:11])[CH2:2]1
Reactant: Oc1ccccc1O
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(C(=O)Oc2ccccc2O)C1

Procedure:
p-Menth-3-oyl chloride (2.0 g.) and pyrocatechol (1.1 g.) were heated under refluxing conditions in toluene (75 ml.) for 4 hours. An oily liquid was recovered which was identified as ortho-hydroxyphenyl p-menthane-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K7) (246 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white amorphous substance (352 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>CCCCCC>[CH:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCCCC1
Reactant: C1CCNC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Product: C1CCCC(N2CCCC2)CCC1

Procedure:
A three-neck 3000 ml. flask is charged with 75 gm. (1.05 moles) of pyrrolidine, 51 gm. cyclooctanone (0.4 mole) and 80 ml. anhydrous hexane. To the resulting solution, 80 gm. (0.8 mole) of anhydrous magnesium sulfate is added and the mixture is mechanically stirred and heated at reflux (the reaction was monitored by NMR analysis) for 108 hours. The reaction mixture is filtered through a fritted glass funnel. The filtrate is concentrated at reduced pressure on a rotary evaporator to give 70.5 gm. of a clear (yellow-tinted) oily substance. 1H-NMR and 13C-NMR spectra are acceptable for the desired product, 1-(1-pyrrolino)cyclooctene. Saturation of the 1-(1-pyrrolino)cyclooctene to give N-cyclooctylpyrrolidine is accomplished in 98% yield by catalytic hydrogenation in ethanol at a 55 psi pressure of hydrogen gas in the presence of 10% Pd on activated carbon.