Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17]>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1OC
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: C1COCCO1
Product: COc1ccc(NS(=O)(=O)c2cccnc2Cl)cc1OC
Yield: 45.3 %

Procedure:
A solution of 2-chloropyridine-3-sulfonyl chloride (500 mg, 2.36 mmol) and 3,4-dimethoxyaniline (397 mg, 2.59 mmol) in 1,4-dioxane (10 mL) was stirred for 1 h at 0° C. The reaction mixture was filtered, the residue washed with ether and the filtrate concentrated in vacuo. Purification by gradient column chromatography eluting with 10-60% EtOAc in iso-hexane yielded the title compound (352 mg, 1.07 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:29])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:10]=[C:9]([NH2:29])[C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: N#CC(c1ccccc1)c1ncccc1Br
Solvent: ClCCl
Product: Nc1nn2cccc(Br)c2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3-Bromo-pyridin-2-yl)-phenyl-acetonitrile (0.528 g, 1 eq) was dissolved in DCM (5 mL) and the solution cooled to 0° C. O-(Mesitylsulfonyl)hydroxylamine (0.540 g, 1 eq) was added portion-wise and the reaction was stirred at 0° C. for 2 h then stored at 4° C. for 16 h. An additional portion of 0-(mesitylsulfonyl)hydroxylamine (Intermediate 2, cf above) was added and the reaction mixture stirred at 0° C. for 2 h. The precipitate was collected by filtration and washed with pet ether 40-60 yielding the intermediate aminopyridine salt. The residue was re-dissolved in DCM/water and the aqueous was extracted with DCM (×3). The combined organics were dried and concentrated in vacuo to afford the expected product.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:16])NC1C=C(C=CN=1)C(O)=O)([CH3:3])[CH3:2].NC1C=C(C=CN=1)C(OCC)=O.[NH:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([O:40]C)=[O:39])[C:32]=2[CH:31]=[CH:30]1>>[CH:1]([NH:4][C:5]([N:29]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([OH:40])=[O:39])[C:32]=2[CH:31]=[CH:30]1)=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)Nc1cc(C(=O)O)ccn1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CCOC(=O)c1ccnc(N)c1
Product: CC(C)NC(=O)n1ccc2c(C(=O)O)cccc21

Procedure:
This compound is prepared analogously to Intermediate Y by replacing ethyl 2-aminoisonicotinate in step 1 with methyl indol-4-carboxylate; [M+H]+ 247
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][C:57]([C:59]1[N:60]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[C:61]2[C:66]([C:67](=[O:79])[C:68]=1[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76](=[O:78])[CH3:77])=[CH:72][CH:71]=1)=[CH:65][CH:64]=[C:63]([CH3:80])[N:62]=2)=[O:58]>CO>[CH3:55][O:56][C:57]([C:59]1[N:60]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[C:61]2[C:66]([C:67](=[O:79])[C:68]=1[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76](=[O:78])[CH2:77][Br:1])=[CH:72][CH:71]=1)=[CH:65][CH:64]=[C:63]([CH3:80])[N:62]=2)=[O:58]
Reactant: [Br-]
Reactant: COC(=O)c1c(Cc2ccc(C(C)=O)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1c(Cc2ccc(C(=O)CBr)cc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrabutylammonium tribromide (72 mg, 0.15 mmol) was added to a solution of 3-(4-acetylbenzyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (53 mg, 0.12 mmol) in MeOH (8 mL), and the resulting mixture stirred at RT overnight. The reaction mixture was concentrated under reduced pressure, and the crude residue purified by preparative TLC (EtOAc/hexane, 10/90) to afford 23 of 3-[4-(2-bromoacetyl)-benzyl]-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester as an off-white powder. MS=507 [M+H]+; MP=189.0-191.1° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N[C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C.C(O)(=O)C.C(N(CC)CC)C.C(#N)C>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[C:22]([C:1]([NH2:8])=[O:2])[CH:23]=1.[C:1]([NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: Nc1cnc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc2ccccc2c1

Procedure:
A solution of N-Boc-D-Homophenylalanine (3.0 g, 10.7 mmol) in ethyl acetate (100 mL) was treated with 3-aminoquinoline (3.08 g, 21.4 mmol) followed by dicyclohexylcarbodiimide (2.31 g, 11.2 mmol). The reaction was stirred at 25° C. for 3 hr (HPLC monitoring RP-18, 250×4 mm, water:acetonitrile:triethylamine:acetic acid=500:500:0.6:1 (mL), UV detector, λ=254 nm), filtered and the filtrate washed with 1M hydrochloric acid (25 mL), saturated solution of sodium bicarbonate (25 mL) and water (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford title compound (4.3 g) as white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22].CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:15][C:16]1[C:17]([S:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[CH:18][C:19]([F:25])=[C:20]([CH:24]=1)[C:21]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:22]
Reactant: O=C(O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
N,N-Diisopropylethylamine (0.248 mL, 1.422 mmol) and methansulfonamide (135 mg, 1.42 mmol) were added to a mixture of 5-chloro-4-(3,4-dichlorophenylthio)-2-fluorobenzoic acid (Preparation 159, 250 mg, 0.71 mmol), 4-dimethylaminopyridine (130 mg, 1.07 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (204 mg, 1.07 mmol) in DCM (4.4 mL) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated to dryness and the residue taken up in EtOAc (30 mL), washed with 1N aq. HCl (2×5 mL), brine (4×5 mL), dried over MgSO4, filtered and evaporated to give a yellow solid. The solid was purified using silica gel column chromatography eluting with 19:1 DCM:heptanes to afford the title compound as a white solid (221 mg, 73%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([O:17][C:18](=[O:29])[C@@H:19]([NH2:28])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[CH:12]1([O:17][C:18](=[O:29])[C@@H:19]([NH:28][C:37](=[O:39])[CH3:38])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C[C@H](N)C(=O)OC2CCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(C)cc1)C(=O)OC1CCCC1
Yield: 93 %

Procedure:
To (S)-2-Amino-3-p-tolyl-propionic acid cyclopentyl ester p-toluenesulfonic acid salt prepared in the above stage (10 g, 0.022 mol) was added dichloromethane 200 ml) under nitrogen. Triethylamine (6.29 ml, 0.044 mol) was added dropwise with stirring. Acetyl chloride (1.72 ml, 0.022 mol) in dichloromethane (50 ml) was added dropwise to the reaction. Acetyl chloride (0.1 ml) in DCM (0.5 ml) was added after 20 mins and the reaction reached completion after 1 hr. The organic phase was washed with saturated sodium bicarbonate (3×200 ml), dried (Na2SO4) and the solvent removed in vacuo. The required product was obtained 6.62 g, 93% yield and was used in the next step without further purification. m/z 321 [M++H]+
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Temperature: -25 °C

Procedure:
A solution of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 2.98 g, 6.29 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 1.10 g, 5.72 mmol) in THF (45 ml) at −70° C. (dry ice/2-PrOH bath, internal temperature) under argon was treated with LHMDS (1 M in THF, 12.6 ml, 12.6 mmol). The resulting solution was stirred with cooling for 35 min. The cooling bath was then removed and the reaction mixture was allowed to warm to −25° C., before being re-cooled to −70° C. The resulting solution was quenched with sat. aq. NH4Cl, allowed to warm to room temperature and extracted twice with EtOAc/heptanes 1:1. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated and dried under vacuum to give the title compound as a white solid. (UPLC-MS 3) tR 1.60; ESI-MS 571.4 [M+H]+. 1H NMR (400 MHz, CDCl3-d) δ 13.81 (s, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 5.45 (s, 1H), 5.26 (br s, 1H), 4.87 (s, 2H), 4.07-3.99 (m, 2H), 3.63 (t, 2H), 3.52-3.38 (m, 11H), 2.86 (t, 2H), 2.05-1.94 (m, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F

Procedure:
The solid 1-(5-amino-2,4-dichlorophenyl)-4,5-dihydro-4-difluoromethyl-3-methyl-1,2,4-triazol-5(1H)-one (1.0 equiv.) and 1.2 equiv of methanesulfonyl chloride was suspended in 20 equivalent of water and the reaction mixture chilled to 10 C. Vigorous stirring was commenced and 0.05 equiv of tetrabutylammonium bromide in 0.05 equiv of toluene was added. Using a pH meter, the pH of the suspension was brought to 7.8 by adding adequate quantity of 1 molar sodium carbonate aqueous solution and dynamically maintained for 1 hour. The suspension was much reduced but not eliminated. Concentrated hydrochloric acid was added slowly to bring the pH of the reaction to 2.0 Wherein a precipitate was formed. The precipitate was collected by filtration, washed with water and dried to give the N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl]methanesulfonamide as a white solid (0.41 equiv and 91% purity).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH:9]([CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:6]=2[C:5]2[CH2:15][CH2:16][CH:17]([CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)[CH2:18][C:4]=2[C:3]=1[F:28]>C1COCC1.[Pd]>[F:1][C:2]1[C:11]2[O:10][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7][C:6]=2[C:5]2[CH2:15][CH2:16][CH:17]([CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]3)[CH2:18][C:4]=2[C:3]=1[F:28]
Reactant: CCCC1CCC(C2CCc3c4c(c(F)c(F)c3C2)OC(CCC)C=C4)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCc3c(c(F)c(F)c4c3CCC(CCC)O4)C2)CC1

Procedure:
5.0 g (about 11.4 mmol) of 5,6-difluoro-3-propyl-8-(4-propylcyclohexyl)-7,8,9,10-tetrahydro-3H-benzo[f]chromene are hydrogenated at atmospheric pressure in THF and in the presence of Pd/C (5% of Pd). The reaction solution is filtered, and the filtrate is evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol, giving a 1:1 mixture of isomeric 5,6-difluoro-3-propyl-8-(4-propylcyclohexyl)-2,3,7,8,9,10-hexahydro-1H-benzo[f]chromenes (m.p. 89° C.). This can be resolved, for example, by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:31]([C:33]([OH:38])([CH2:36][CH3:37])[C:34]#[CH:35])[CH3:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]([CH2:36][CH3:37])([OH:38])[CH2:34][CH3:35])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(O)(CC)CC
Solvent: CC#N
Solvent: O
Product: CCC(O)(C#Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1)CC

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (82) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 3-ethylpent-1-yn-3-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J=8 Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.30 (m, 2H), 5.17 (s, 1H), 2.59 (s, 3H), 1.69 (m, 4H), 1.01 (m, 6H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 3.5 min run): tR (min)=2.64.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:33](C)[C:34](=O)C(F)(F)F)=[C:6]([CH:32]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:8].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:33][CH3:34])=[C:6]([CH:32]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:27][CH:28]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1)=[O:8]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Yield: 95.8 %

Procedure:
35 mg of 5-chloro-N-(4-cyclopropyl-benzyl)-2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide were dissolved in 1 ml methanol and 0.06 ml 1N aqueous NaOH and heated to 55° C. for 5 hours. The mixture was then concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered off and concentrated in vacuo, to give 28 mg (96%) 5-chloro-N-(4-cyclopropyl-benzyl)-2-methylamino-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a light yellow viscous oil. (ISP) 503.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.OS(O)(=O)=O.[CH3:20]O>>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]

Procedure:
To a solution of 4,5-difluoro-2-nitrobenzoic acid 1a (40.0 g, 196.947 mmol) in anhydrous MeOH (1.0 L), was added concentrated H2SO4 (60.0 mL) and the clear mixture was refluxed for 2 days. Then methanol was removed in vacuo and the residue was partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried over with anhydrous. Na2SO4, and concentrated to yield the methyl 4,5-difluoro-2-nitrobenzoate 1b as a pale yellow solid, 39.71 g (93%).
Reaction SMILES: CN(C)[C@@H]1CCCC[C@H]1O.[H-].[Na+].CS(Cl)(=O)=O.CNCC1C=CC=CC=1.[CH3:27][N:28]([CH3:44])[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[N:35](C)[CH2:36]C1C=CC=CC=1>[Pd].CCO.C1COCC1>[CH3:27][N:28]([CH3:44])[C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[NH:35][CH3:36]
Reactant: CN(C)C1CCCCC1N(C)Cc1ccccc1
Agent: [Pd]
Agent: CN(C)[C@@H]1CCCC[C@H]1O
Agent: CNCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@@H]1CCCC[C@H]1N(C)C
Reaction time: 18 h

Procedure:
A solution of trans-2-dimethylaminocyclohexanol (61,1 g.; 0.427 mole) in 85 ml. of THF was added during 5 minutes to a suspension of NaH (17.97 g; 0.427 mole of 57% dispersion in mineral oil) in 250 ml. of THF, and the mixture was heated at 95° for 2 hours. It was cooled to 10°, and treated dropwise with methanesulfonyl chloride (48.91 g.; 0.427 mole) during 40 minutes keeping the temperature at 15°. N-Methylbenzylamine (103.48 g.; 0.854 mole distilled) was then added, THF was evaporated and heating continued at 95° for 18 hours. The mixture was treated with 500 ml. of 20% NaOH, heated at 95°, cooled and extracted with ether (6 ×100 ml.). The ether solution was extracted with 10% HCl (6 ×100 ml.), backwashed with ether (discard ether), cooled, basified with 20% NaOH and extracted with ether. The ether extract was washed with H2O, saturated salt solution, dried (MgSO4) and evaporated to give 48.6 g. of crude N,N,N'-trimethyl-N'-benzyl-1,2-cyclohexanediamine as an oil. A solution of this oil (46.6 g.) was hydrogenated in two portions each in 130 ml. of EtOH, with 2.6 g. of 10% Pd-C and 28.6 g. of 70% HCLO4 at initial pressure of 51 p.s.i. for 22 hours. The mixture was filtered through Celite, the filtrate was evaporated, cooled in ice and bssified with 40% KOH. The resulting thick suspension was extracted with ether (4 ×200 ml.), the ether extract was dried (MgSO4) and evaporated. The product boiled at 87°-88° (15 mm.) Vpc-mass spectrum showed that the first peak 3.4 minutes, was N,N-dimethyl-1,2-cyclohexanediamine and the second peak (4.1 minute) was the desired N,N,N'-trimethyl-1,2-cyclohexanediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[S-:19][C:20]#[N:21].[K+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=2)[C:20]([NH2:21])=[S:19])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(O)c1ccc(CNc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Product: NC(=S)N(Cc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Yield: 74.1 %

Procedure:
A mixture of 4-[(4-chlorophenylamino)methyl]benzoic acid (33.3 g, 127 mmol) and potassium thiocyanate (37 g, 382 mmol) in 1 N hydrochloric acid (500 mL) was refluxed for 16 hours. The suspension was filtered and washed with water. The solid was mixed with potassium thiocyanate (37 g, 382 mmol) and 1 N hydrochloric acid (500 mL) and the mixture was again refluxed for 16 hours. Filtration, washing with water and re-submission to the reaction conditions above afforded 30.2 g (70%) of 4-[1-(4-chlorophenyl)thioureidomethyl]benzoic acid as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7]CC)=O.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[C:29](#[N:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:4]=1[C:5](=[O:7])[NH:38][C:29]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[CH:14]2
Reactant: COc1ccc(C#N)cc1
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cccc(OC)c3c(=O)[nH]2)cc1
Reaction time: 0.75 h
Yield: 13.7 %

Procedure:
Ethyl 2-methoxy-6-methylbenzoate (5.011 g) was dissolved in tetrahydrofuran (20 ml), followed by the addition of 1.5M lithium diisopropylamide/cyclohexane solution (19 ml) in nitrogen atmosphere at −70° C. The resulting mixture was stirred for 45 min. Anisonitrile (3.462 g)/tetrahydrofuran (10 ml) solution was added to the reaction mixture. The cooling bath was removed, and then the mixture was stirred for 100 min. An aqueous solution of saturated ammonium chloride and ethyl acetate were added to the reaction solution, and the mixture was stirred for 30 min. The resulting insoluble matters were collected by filtration, and then washed with ethyl acetate and water, to give the title compound as a pale yellow solid (991 mg, yield; 13%).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[C:17]([OH:24])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:24][C:17]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:6][C:5]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)c2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution containing 39.96 g of 4,5-dichloro-2-nitrotoluene and 39.30 g of 4-chloro-5,6,7,8-tetrahydro-1-naphthol in 250 ml of DMF under an atmosphere of nitrogen and at room temperature was added 3.87 g of anhydrous potassium carbonate. The resulting mixture was then heated to 110° C. After 20 hrs at 110° C., the reaction mixture was cooled to room temperature. The DMF was removed in vacuo. The residue was dissolved in 500 ml of warm toluene and filtered through celite. The filter cake was thoroughly washed with toluene. The solvents from the combined filtrates were removed to afford 67.04 g of tan powder. This material was recrystallized from a hexane-ethyl acetate mixture to afford 49.46 g of the desired product as light tan crystals. mp 139°-140° C. NMR (CDCl3): 1.6-1.9 (m, 4H), 2.4-2.9 (m, 7H, contains singlet at 2.45), 6.51 (s, 1H), 6.73 (d, J-8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].C([O-])(=O)C.[Na+]>[Pd]>[CH3:18][C:5]1[CH:4]=[CH:3][CH:2]=[C:11]2[C:6]=1[C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][NH:10]2
Reactant: CCOC(=O)c1c[nH]c2c(Br)ccc(C)c2c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)c1c[nH]c2cccc(C)c2c1=O
Reaction time: 4 h
Yield: 21.7 %

Procedure:
A flask charged with ethyl 8-bromo-5-methyl-4-oxo-1H-quinoline-3-carboxylate (895 mg, 2.89 mmol), sodium acetate (237 mg, 2.89 mmol) and Pd/C (180 mg, 1.69 mmol) was flushed under a N2 followed by evacuating under vacuum. Acetic acid (21 mL) was added under an inert atmosphere followed by evacuating under vacuum. The reaction was then stirred for 4 h in an atmosphere of H2. The reaction was filtered to remove the Pd catalyst and the solvent was evaporated to give ethyl 5-methyl-4-oxo-1H-quinoline-3-carboxylate (145 mg, 22%).