Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:14])(=[O:13])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:2]([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: O=S1(=O)NC(Cl)=Nc2ccc(Cl)cc21
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred suspension of 10.0 g of 3,7-dichloro-2H-1,2,4-benzothiadiazine 1,1-dioxide in 100 ml of water is added 8.0 g of 1-methylpiperazine, while the mixture is cooled in an ice bath. After the addition, the mixture is stirred at 60° C. for 1 hour. The crystalline precipitate collected is recrystallized from a mixture of dimethylformamide and water to give 11.0 g of the desired product, m.p. above 300° C.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH:14]=[CH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1>>[O:18]=[C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH:22]=[CH:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Agent: Cl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5ccc(=O)[nH]c45)CC3)nc2[nH]1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 446.2 (Exact Mass: 445.21).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[CH2:15][O:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(O)(C)C>[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:13]([OH:14])[CH2:15][NH:4][CH2:3][CH2:1][OH:2])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: Clc1ccc([C@@H]2CO2)cc1Cl
Reactant: NCCO
Solvent: CC(C)O
Product: OCCNC[C@H](O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
In a 3 neck flask equipped with a mechanical stirrer, thermocouple and addition funnel in an ambient temperature water bath was added ethanolamine (330 mL, 5.47 mol). (R)-2-(3,4-dichlorophenyl)oxirane (184 g, 976 mmol) in isopropanol (75 mL) was added dropwise over 1 h. Reaction temperature stayed <30° C. during addition. The reaction mixture was stirred at ambient temperature for 14 h, diluted with 2000 mL of ice water and extracted three times with 1000 mL of ethyl acetate. The combined organic phases were dried over MgSO4, filtered over Celite and concentrated in vacuo affording (1R)-1-(3,4-dichlorophenyl)-2-(2-hydroxyethylamino)-ethanol (244 g, 100%) as a white semi-solid. 1H-NMR (400 MHz, CDCl3) δ 7.58-7.54 (m, 2H), 7.35-7.32 (m, 1H), 5.51 (s, 1H), 4.64 (dd, J=5.0, 7.2 Hz, 1H), 4.49 (s, 1H), 3.43 (dd, J=5.0, 10.4 Hz, 2H), 2.69-2.50 (m, 4H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=250.3; tR=0.84 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:13]C(=O)C(F)(F)F)[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1>C(O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([OH:13])[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2)=NC1OC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2)=NC1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.3 %

Procedure:
A suspension of 10 g (0.023 mole) of 7-bromo-1,3-dihydro-5-phenyl-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-one in a mixture of 130 ml ethanol and 130 ml of 5% aqueous sodium bicarbonate was stirred at room temperature (25°) for 20 hr. The suspended solid was then collected on a filter, washed with water, and recrystallized from ethanol to give 6.5 g (85%) of 7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless plates: mp 190°-192°; 1H nmr (DMSO-d6) δ 4.86 ppm (1H), 6.27 ppm (1H, OH), 7.18-7.90 ppm (m, 8H).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>O1CCCC1>[CH3:17][CH:15]1[O:16][CH:11]([CH3:10])[CH2:12][N:13]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14]1
Reactant: N#Cc1cccnc1F
Reactant: CC1CNCC(C)O1
Solvent: C1CCOC1
Product: CC1CN(c2ncccc2C#N)CC(C)O1
Yield: 19.6 %

Procedure:
A solution of 2-fluoro-nicotinonitrile (1.06 g, 8.69 mmol) and 2,6-dimethyl-morpholine (1.0 g, 8.69 mmol) in tetrahydrofuran (10 ml) was heated at 110° C. for 10 min in a microwave reactor. The reaction mixture was concentrated and purified by flash column chromatography using hexanes:ethylacetate (2:1) to yield 0.37 g (40%) of product. MS (ESI4) m/z 218 (M+H)+;
Reaction SMILES: [N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH:26](C)[CH3:27])=[O:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:31](N(CC)CC)C.C(=O)(OC1(C)CC1)ON1C(=O)CCC1=O>ClCCl>[N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]4([CH3:31])[CH2:26][CH2:27]4)=[O:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCN(CC)CC
Reactant: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Agent: CC1(OC(=O)ON2C(=O)CCC2=O)CC1
Solvent: ClCCl
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4cnnn4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step B, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). 2,5-Dioxopyrrolidin-1-yl 1-methylcyclopropyl carbonate (81 mg, 0.38 mmol) was added. The mixture was stirred at RT for 30 min and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 1 L). The product containing fractions were combined and concentrated under reduced pressure. The compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min) to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.30-3.90 (m, 4H), 2.80-2.60 (m, 2H), 2.25-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.55 (s, 3H), 1.40-1.20 (m, 2H), 1.10-0.80 (m, 4H), 0.80-0.55 (m, 4H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 412 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:27][CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cccnc1
Reactant: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CN(CCCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 90 mg, 0.185 mmol), pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol) and Na2CO3 (59 mg, 0.554 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.5 mg, 0.0092 mmol) and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.05 min, m/z=447.1 [M+H]+, m/z=445.2 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>O1CCCC1>[CH2:55]([O:54][C:52](=[O:53])[CH2:51][O:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:21])[CH3:22])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH3:56]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a stirred solution of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-{[(1-isopropyl-1H-indazol-3-yl) carbonyl]amino}pyrrolidine-1-carboxylate (358 mg, 0.89 mmol, step 2 of Example 7) in tetrahydrofuran (7 mL) was added sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) at 0° C. Then to the solution was added 18-crown-6 (164 mg, 0.45 mmol) and a solution of ethyl bromoacetate (446 mg, 2.67 mmol) in tetrahydrofuran (5 mL) at 0° C. It was stirred overnight rising to room temperature. The resulting mixture was quenched by addition of water and it was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 310 mg (71%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])=[CH:12][N:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])=[CH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCCCCCCCC(=O)Oc1cnc(-c2ccc(C(C)=O)cc2)nc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(=O)Oc1cnc(-c2ccc(C(C)O)cc2)nc1
Yield: 33.8 %

Procedure:
The procedure of Referential Example 11 was followed except for use of 38.3 g (0.1 mol) of 2-(4-acetylphenyl)-5-decylcarbonyloxypyrimidine in place of 35.5 g of 2-(4-acetylphenyl)-5-decyloxypyrimidine, forming an asymmetric hydrolyzate by use of an enzyme to obtain 13 g of (+)-2-(4-(1-hydroxyethyl)phenyl)-5-decylcarbonyloxypyrimidine (II-a-12), [α]D20 =+24.5° (c=1, chloroform).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([Cl:17])[CH:11]=2)=[O:7])[CH3:4].Br[CH:19]([CH3:22])[C:20]#[N:21]>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH:19]([C:20]#[N:21])[CH3:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([Cl:17])[CH:11]=2)=[O:7])[CH3:4]
Reactant: CC(Br)C#N
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C(C)C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Sodiumhydride (0.89 g, 20.1 mmol) was suspended in dimethylformamide (15 mL) and a solution of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (2.00 g, 8.9 mmol) in dimethylformamide (8 mL) was added at 0° C. The mixture was stirred for 1 h at 0° C. then 2-bromo-propionitrile (3.6 g, 23.95 mmol) was added. After 1 h at room temperature the mixture was heated at 75° C. for 18 hours. The reaction mixture was then added to an ice/water mixture (100 mL) and extracted with ethylacetate. The organic phases were pooled washed with brine, dried with Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel (ether/n-hexane 1:4) yielded 6-chloro-1-(cyano-methyl-methyl)-1H-indole-2-carboxylic acid ethyl ester (2.06 g, 67%) as a colorless solid, MS: m/e=277.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]=1[NH2:6])([O-])=O>CCOC(C)=O.[Pd]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([NH2:1])[C:5]=1[NH2:6]
Reactant: Nc1c(-c2ccccn2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ccccn2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 103000 %

Procedure:
To a solution of 2-nitro-6-(pyridin-2-yl)aniline (XCIX) (2.4 g, 0.01 mmol, 1 eq) in EtOAc (350 mL) was added Pd/C (1 g) and the mixture was stirred at room temperature overnight, filtered and then concentrated in vacuo, to give 3-(pyridin-2-yl)benzene-1,2-diamine (1.9 g, 10.3 mmol, 89% yield) as a yellow oil. ESIMS found for C11H1N3 m/z 186 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1Cl
Temperature: 95 °C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-3-methyl-1,8-naphthyridine (0.4 g, 1.877 mmol), 3,5-difluorophenylboronic acid (0.445 g, 2.82 mmol), Pd(PPh3)4 (0.217 g, 0.188 mmol), potassium carbonate (0.519 g, 3.75 mmol) in toluene (6 mL) and heating at 95° C. for 18 h. Purification by column chromatography (silica gel; 0-25% EtOAc in hexanes) gave 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,8-naphthyridine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([CH3:19])=[N:13]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:19][C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[N:13]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(C)c2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn([C@H]2CC[C@H](C(=O)O)CC2)c(C)c1C

Procedure:
A solution of trans-4-(3,4,5-trimethyl-pyrazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (180 mg, 0.681 mmol) in 1,4-dioxane (6.8 ml) and 2 M aqueous sodium hydroxide solution (3.4 ml, 6.8 mmol) was stirred at room temperature for 3 days. The pH was adjusted to 3 by addition of 2 M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (141 mg, 88%) as light brown solid. MS m/e: 235 ([M−H]−)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:7][C:2]([NH:26][CH2:27][CH2:28][OH:29])=[N:3][CH:4]=1
Reactant: NCCO
Reactant: Fc1ccc(SC(c2cc(F)ccc2F)c2cc(Cl)ncc2Cl)cc1
Solvent: C1COCCO1
Product: OCCNc1cc(C(Sc2ccc(F)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 56 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of 2,5-dichloro-4-[(2,5-difluorophenyl)-(4-fluorophenylthio)methyl]pyridine (200 mg, 0.50 mmol) and 2-aminoethanol (300 μl) was stirred at 120° C. for 2 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (120 mg, 56%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN.[I-:25].[Na+]>O1CCOCC1.N.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:25])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc2C1
Reactant: [I-]
Agent: [Cu]I
Agent: CN(C)CCN
Agent: N
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cc(I)ccc2C1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To 13.0 g (41.6 mmol) 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in 42 mL 1,4-dioxane is added 817 mg (4.21 mmol) copper(I)-iodide under argon. After flushing with argon, 0.89 mL (8.33 mmol) N,N-dimethylethylen-diamine and 12.5 g (83.3 mmol) sodium iodide is added at RT. The reaction mixture is stirred 14 h at 110° C., is cooled to RT and is diluted with 5% aqueous ammonia-solution. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water and is dried over MgSO4, filtered and the solvent is evaporated to give the product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O.C1(C)C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16]
Reactant: O=C(OCCCCl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)OCCCCl)c(N)c1
Yield: 100.4 %

Procedure:
A two liter autoclave was charged with 142 g of (3-chloropropyl)-2,4-dinitrobenzoate, 1275 ml of toluene and 4.5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi hydrogen pressure while maintaining the temperature below 100° C. with cooling. The mixture was cooled and 350 ml of tetrahydrofuran was added to dissolve the solid that had precipitated from the toluene. The resulting solution was filtered to remove the catalyst and the solvents removed at reduced pressure to give 113 g of (3-chloropropyl)-2,4-diaminobenzoate, a white solid, mp 97° C.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:13]=[C:12]([CH3:14])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[N:15]1[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[C:16]1[S:24][CH2:25][C:26]([O:28]CC)=[O:27]>C1COCC1.CO.O>[CH3:3][C:4]1[CH:13]=[C:12]([CH3:14])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[N:15]1[C:19]([C:20]([F:22])([F:21])[F:23])=[N:18][N:17]=[C:16]1[S:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CSc1nnc(C(F)(F)F)n1-c1c(C)cc(C)c2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(-n2c(SCC(=O)O)nnc2C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.436 mL, 0.436 mmol) was added to a solution of ethyl 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetate (0.09 g, 0.218 mmol) in THF/methanol/water (3/3/1, 1.5 mL) and stirred for 18 h at room temperature. The crude reaction mixture was concentrated, acidified with HCl (1M aqueous, 4 mL), and extracted with ethyl acetate (2×3 mL). The combined organics extracts were concentrated to afford 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white foam (0.082 g, 98%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]1[C:12]([NH2:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[CH3:22])[CH:10]=[CH:9][N:8]=1)[CH3:5].[C:23](OC)(=[O:27])[C:24]([CH3:26])=O>>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[C:23](=[O:27])[C:24]([CH3:26])=[N:13][C:12]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:10][CH:9]=[N:8][C:7]1=2)[CH3:5]
Reactant: COC(=O)C(C)=O
Reactant: COCC(C)Nc1nccc(-c2ccc(OC)cc2C)c1N
Product: COCC(C)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3C)ccnc21

Procedure:
N2-(2-Methoxy-1-methyl-ethyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine (0.066 g, 0.22 mmol) and methyl pyruvate (79 μL, 0.88 mmol) were treated substantially as in Part E of Example 67a to give 4-(2-methoxy-1-methyl-ethyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 73a): 1H NMR (300 MHz, CDCl3): δ 8.49–8.47 (d, 1H, J=4.8 Hz), 7.16–7.12 (m, 2H), 6.86–6.82 (m, 2H), 4.41–4.36 (m, 1H), 3.87 (s, 3H), 3.84–3.80 (m, 2H), 3.34 (s, 3H), 2.48 (s, 3H), 2.12 (s, 3H), 1.62–1.60 (d, 3H, J=6.9 Hz). MS (AP) 354.2 [(M+H)+, 100].
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][C:11]1[S:15][C:14]([CH2:16][NH:17][CH:18]=O)=[N:13][CH:12]=1)(=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([O:9][CH2:10][C:11]1[S:15][C:14]2=[CH:16][N:17]=[CH:18][N:13]2[CH:12]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OCc1cnc(CNC=O)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cn2cncc2s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 61116.2 %

Procedure:
A 3.8 ml potion of phosphorus oxychloride was added to 8.7 ml of a toluene solution containing 1.74 g of 5-acetoxymethyl-2-(N-formylamino)methylthiazole, followed by stirring at 100° C. for 2 hours. Then, the solvent was evaporated under reduced pressure, and to the residue, 70 ml of chloroform and 52 ml of an aqueous saturated sodium bicarbonate solution were then added. After stirring, the organic layer was separated. The aqueous layer was extracted with chloroform (26 ml×2). The combined organic layer was combined, and then washed once with the aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 974 g of the title compound.