Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Yield: 57.7 %

Procedure:
N-Phenyl-o-phenylenediamine 13.27 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 14.51 g of product (yield=57.71%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>>[C:3]1([N:8]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:11]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1cccnc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: c1ccc(-n2c(-c3cccnc3)nc3ccccc32)cc1
Yield: 50.1 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and nicotinanilide (119 mg, 0.6 mmol) yielded the title compound as brown solid (68 mg, 50%). mp 110-112° C. 1H NMR (DMSO) δ 7.26 (d, J=7.3Hz, 1H), 7.32-7.63 (m, 8H), 7.86 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.8Hz, 1H), 8.62 (d, J=3.0Hz, 1H), 8.72 (br s, 1H); 13C NMR δ 111.0, 118.7, 123.8, 124.0, 124.4, 125.4, 127.6, 129.5, 130.2, 135.2, 136.4, 137.7, 140.3, 148.6, 149.6, 158.3. HRMS (FAB): cal. for C18H14N3 [M+H+]: 272.1188; found: 272.1180.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=2[CH3:8])[CH:17]=[CH:16][N:15]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 20.2 %

Procedure:
A mixture of 3-bromo-2,4-dimethyl-6-nitropyridine (1.00 g, 4.33 mmol), 2-chloropyridin-4-ol (1.12 g, 8.66 mmol) and K2CO3 (1.79 g, 12.98 mmol) in DMA (5 mL) was sparged with Ar, heated at 105° C. overnight, then cooled to RT. The mixture was diluted with EtOAc, washed successively with 10% K2CO3, 5% LiCl, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (245 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, J=5.2 Hz, 2H), 7.15 (d, J=2.3 Hz, 1H), 7.01 (dd, J=5.8, 2.3 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 280.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]2=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]2[NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c2c(c1O)C(=O)C(c1ccccc1)C2
Reactant: NCc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1O)C(NCc1ccccc1)=C(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.0 Grams of 4,6-dimethyl-7-hydroxy-2-phenyl-1-indanone was dissolved in 10 ml of diethyl ether and 10 ml of dichloromethane, then this solution was added dropwise gradually to a mixture of a solution of 2.55 ml of benzylamine in 10 ml of diethyl ether with 8 g of Molecular sieves 5A. The whole mixture was stirred at room temperature for 2 days and filtered by using Celite to obtain filtrate. The Celite used was washed with dichloromethane and ethanol, then these washing liquors were combined with the above-mentioned filtrate and concentrated. Recrystallized from dichloromethane-ethanol to obtain 3.83 g of 4,6-dimethyl-7-hydroxy-1-benzylamino-2-phenyl-3H-indene. Orange needle-like crystals. Melting point: 214°-215° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=O)=[CH:14]1.Cl.[C:27]1([C:33]2([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:41]3[CH:37]([CH2:38][NH:39][CH2:40]3)[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[C:51]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]3[CH:37]([CH2:38][N:39]([C:23](=[O:25])[CH2:22][C:15]4[C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[NH:13][CH:14]=4)[CH2:40]3)[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])([OH:42])[CH2:35][CH2:34]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
0.41 g of cabonyldiimidazole is added to a solution of 0.44 g of 3-indolylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred at room temperature for 1 hour and a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry dichloromethane and then 0.7 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of dichloromethane, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, and is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (35/65 by volume) and collecting-fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in diisopropylether. 0.17 g of (3aRS,4RS,7aRS)-7,7-diphenyl-2-(3-indolylacetyl)-4-(2-methoxyphenyl)perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][CH2:7][C@@H:8]([CH3:15])[CH2:9]OS(C)(=O)=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][S:21]([O-:23])=[O:22].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([CH3:15])[CH2:9][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:16][C:17]=1[CH3:18]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(OC[C@@H](C)COS(C)(=O)=O)cc(C)c1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC[C@@H](C)CS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C

Procedure:
Methanesulfonic acid (R)-3-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl ester (148 mg) and sodium methanesulfinate (215 mg) are stirred in 3 mL of N,N-dimethylformamide at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound. Yield: 118 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[C:3]([Cl:9])=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl

Procedure:
the reaction of 1,2,3-trichlorobenzene with a nitration reagent, in particular nitric acid, to give 2,3,4-trichloronitrobenzene (A),
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][C:34]([CH3:63])([O:36][C:37](=[O:62])[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.NC1C=CC(N(CC)CC)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:56]([C:55]2[CH:54]=[C:53]([CH2:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][C:37]([O:36][C:34]([CH3:63])([CH3:35])[CH3:33])=[O:62])[CH:61]=[CH:60][CH:59]=2)=[O:57])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.42 h
Yield: 77.3 %

Procedure:
To a solution of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (1.77 g, 4.0 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (1.70 g, 3.86 mmol) and DIPEA (1.47 g, 11.4 mmol) in DMF (20 ml) was added HATU (1.56 g, 4.10 mmol). The reaction mixture was stirred for 30 minutes, at which time additional 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (0.06 g, 0.14 mmol) was added. After stirring an additional 25 minutes, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (200 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (50% to 100% EtOAc in hexanes) gave the title compound (2.58 g) as an oil.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C(OCC)(=O)C>O1CCCC1>[C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=[S:26])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=S)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.9 %

Procedure:
A solution of Example 120A (0.5 g, 2.2 mmol) in tetrahydrofuran (10 mL) was added Lawesson's reagent (0.53 g, 1.3 mmol). After stirring at room temperature for 5 hours, the reaction mixture was poured into ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Analogix® Intelliflash280™, SiO2, 0-100% of ethyl acetate in hexanes) to obtain 0.33 g of the title compound. MS (ESI+) M/Z 245 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=3)=[O:28])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 3.77 g, 15 mmol) in THF (55 ml) under N2-atmosphere, 4-tertbutylphenyl isocyanate (5.26 g, 30 mmol) dissolved in THF (5 ml) is added. During stirring for 1 h at rt a suspension is formed. The mixture is then re-dissolved in AcOEt and a solution of NaHCO3 in water, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Stirring of the resulting solid in Et2O finally yields the title compound: m.p.: 111-112° C.; 1H-NMR (DMSO-d6): 8.75 (s, HN), 8.65 (s, 1H), 8.62 (s, HN), 7.51 (d, 2H), 7.36 (d, 2H), 7.33 (s, 1H), 7.31 (d, 2H), 7.17 (d, 2H), 1.27 (Me3C).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:4]([F:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cc(F)c(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(F)c2)C1=O
Yield: 66.5 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.23 g) described in Preparation Example 111 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (912 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][CH:13]([CH3:31])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]>>[CH3:12][CH:13]([CH3:31])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=3[Cl:1])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,4-dichlorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (90% yield). 5H NMR (500 MHz, CS(C13) δ 8.07, 7.85, 7.47, 7.35, 7.28, 7.01, 4.02-4.09, 3.75-3.93, 3.33-3.52, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 450 (M).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 10.4 g (55.2 mmol) of 4-bromothiophenol and 6.49 g (55.4 mmol of ethyl acrylate in 5 mL of dichloromethane was added 4.13 g (41 mmol) of triethylamine at 0° C. under argon. The resulting solution was warmed to room temperature and stirred for 12 hours. The solution was then treated with 50 mL 10% aqueous NaOH and the product extracted into 3×100 mL ether.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[CH3:14][C:15]1[O:19][N:18]=[C:17]([C:20](O)=O)[CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:20]([C:17]3[CH:16]=[C:15]([CH3:14])[O:19][N:18]=3)[N:4]2[N:3]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: NNc1nnc(Cl)c2ccccc12
Product: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1

Procedure:
Intermediate 14b was prepared in two steps from intermediate 11 in an analogous fashion to the preparation of intermediate 14a (see Example 1). Commercially available 5-methylisoxazole-3-carboxylic acid (12c) was used in the first step.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([CH3:21])=[C:10]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>O1CCCC1.CO>[Br:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([CH3:21])=[C:10]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCN(c1cc(Br)c(F)c(C(=O)OC)c1C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1cc(Br)c(F)c(C(=O)O)c1C)C1CCOCC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 105.1 %

Procedure:
To a solution of methyl 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoate (519 mg, 1.39 mmol) in Tetrahydrofuran (13 ml) and MeOH (4 ml) was added 4M NaOH (13.87 ml). The reaction mixture was stirred at 50° C. in air for 72 hours. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×15 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 526 mg (95%) of 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoic acid as a beige foam. LC-MS 88%, 1.77 min (3 minute LC-MS method), m/z=359.9/361.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.43-7.31 (m, 1H), 4.00 (d, J=11.3 Hz, 2H), 3.41-3.29 (m, 2H), 3.16-2.91 (m, 3H), 2.40 (s, 3H), 1.84-1.59 (m, 4H), 0.99-0.82 (m, 3H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:40][C@:41]2(C)[CH2:43][O:42]2)(=O)=O)C=CC=1)([O-])=O.CN(C=O)C>O>[C:1]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:40][C@@H:41]2[CH2:43][O:42]2)[C:13]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:11]=1[Cl:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1O)c1ccccc1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)c(OC(=O)c2ccccc2)cc1OC[C@@H]1CO1)c1ccccc1
Yield: 98.6 %

Procedure:
To a stirred solution of 4-(benzoylamino)-2-chloro-5-hydroxyphenyl benzoate (103 mg, 0.28 mmol) and [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (73 mg, 0.28 mmol) in DMF (3 mL) cesium carbonate (98 mg, 0.3 mmol) was added. The stirring was continued at ambient temperature over night. The mixture was poured into water and partitioned between water and ethylacetate. The organic phase was washed with water, dried and concentrated in vacuo to give a white solid (117 mg, 98%). The solid was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:6]=[CH:5]2.C([Li])CCC.[B:37](OC)([O:40]C)[O:38]C>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([B:37]([OH:40])[OH:38])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)([C:28]([CH3:31])([CH3:29])[CH3:30])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](OCCCn1ncc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCn1ncc2cc(B(O)O)ccc21)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
5-Bromo-1-[3-(tert-butyl-diphenylsilanyloxy)-propyl]-1H-indazole (3s) (200 mg, 0.41 mmol) was dissolved in 4.0 mL THF and cooled to −78° C. A solution of n-butyl lithium in hexanes (2.5M, 0.17 mL) was added slowly. The yellow solution was stirred for 30 minutes. Trimethyl borate (130 mg, 1.2 mmol) was added and the reaction was warmed to room temperature and stirred for 30 min. The reaction was quenched with 10 mL of a 0.3% aqueous HCl solution and the resulting mixture was stirred for 30 min. The reaction was diluted with Et2O and the layers were separated. The organic phase was washed with brine. The aqueous phases were extracted once with Et2O. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was partially purified on silica gel with 3% MeOH/CH2Cl2 to afford (4s) (97 mg, 52%). MS (ESI+) m/z 459 (M+H)+. HPLC (5 to 95%) 3.74 min. This mixture was carried on to the next step without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccccc3Cl)c2O1

Procedure:
Treatment of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.6 g, 6.26 mmol) with sodium azide (1.63 g, 25.05 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.17 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.05 g (57%) of (±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.71; H, 5.48; N, 4.55.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]([N+:24]([O-:26])=[O:25])[CH3:23])[CH:18]=3)[CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].BrC1C=C2C(=CC=1)C([C:38]([F:41])([F:40])[F:39])=C(O[C@H]1CC[C@H](C(C)(C)C)CC1)C=C2>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]([N+:24]([O-:26])=[O:25])[CH3:23])[CH:18]=3)[C:13]=2[C:38]([F:41])([F:40])[F:39])[CH2:7][CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2C(F)(F)F)CC1
Product: CC(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
2-(trans-4-tert-butylcyclohexyloxy)-6-(1-nitroethyl)-1-(trifluoromethyl)naphthalene was synthesized as per 2-(trans-4-tert-butylcyclohexyloxy)-6-(1-nitroethyl)naphthalene (Example 204) in 35% yield using 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene as starting material.