Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:22]1[CH:21]=[C:20]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH2:11])=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:24]=[N:23]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Nc1nc2ccc(Br)nc2s1
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2ccc(-c3cn[nH]c3)nc2s1
Temperature: 150 °C

Procedure:
To a microwave vial, 5-bromothiazolo[5,4-b]pyridin-2-amine (1B, 100 mg, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5A, 2.0 equivalent), Na2CO3 (4.0 equivalents), DMF (0.15 M) and H2O (0.73 M) were added. While mixture was under N2, Pd(PPh3)4 was added and the mixture was then heated in a microwave for 3 h at 150° C. The crude mixture was filtered, and purified by preparatory LCMS. Intermediate 5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine (5B) was obtained as a white solid. ESI-MS: m/z 218.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([N:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Li]CCCC.[B:28](OC)([O:31]C)[O:29]C.Cl>C1COCC1>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([N:6]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:5]2[CH:4]=[CH:3][C:2]([B:28]([OH:31])[OH:29])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-N,N-di-p-tolylaniline (Compound 25) (12.55 g, 35.6 mmol) in anhydrous THF (100 mL), was added n-BuLi solution (16 mL, 2.5 M in hexanes) at −78° C. slowly. The resulting solution was stirred at −78° C. for about one hour. Then a freshly distilled trimethyl borate (B(OCH3)3) (5.6 mL) was added. The solution turned to yellow immediately, and was stirred at RT for about 2 hours. After addition of 1N HCl solution (150 mL), the whole was stirred at RT for about 18 hours and concentrated. The resulting solid was filtered and washed with diethyl ether to give a light yellow solid (Compound 26) (5.8 g, in 56% yield).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])(=[O:33])=[O:32]
Reactant: CCC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of 0.084 g (0.28 mmol) of the product (24) from Step 8 and 0.08 mL (0.56 mmol) of triethylamine in 2.5 mL of anhydrous DCM was cooled to 0° C. Then was added dropwise 0.03 mL (0.34 mmol) of methanesulfonyl chloride and the resulting mixture was allowed to warm to ambient temperature under nitrogen. Excess DCM was added and the reaction mixture was washed with water, saturated NaHCO3 and brine. The organic layer was then dried over MgSO4 and the solvent was removed in vacuo yielding 0.106 g (0.28 mmol, 100%) of 1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)propyl methanesulfonate (25) as a tan oil.
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:27]([O:28][CH3:29])=[CH:26][C:10]2[N:11]([CH3:25])[C:12](=[O:24])[CH2:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:9]=2[CH:8]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.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>[CH3:29][O:28][C:27]1[C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]2[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])=[N:14][CH2:13][C:12](=[O:24])[N:11]([CH3:25])[C:10]=2[CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1-c1ccccc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Temperature: 120 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To 5 mL of degazed DMF were added 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 (200 mg, 0.52 mmol), benzene boronic acid (160 mg, 1.32 mmoles), tripotassium phosphate (300 mg, 1.42 mmol), Pd(PPh3)4 (30 mg, 0.03 mmoles). The mixture was stirred for 16 hours at 120° C. under nitrogen atmosphere. The working solution was diluted ten times with water and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was chromatographied: eluant: CH2Cl2/Et2O: 1/1. The obtained compound was crystallised from ether/pentane to afford the title compound (118 mg): white solid, (yield=60%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:11]([C:13]1(F)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH2:14]1)#[N:12]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: N#CC1(F)CC=Cc2ccccc21
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC3(CC2)OCCO3)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.2 %

Procedure:
1.4-dioxa-8-azaspiro[4.5]decane (332 mg, 2.32 mmol) was added to a solution of 1-cyano-1-fluoronaphthalene (120 mg, 0.70 mmol) in anhydrous THF (1 mL). After 48 hours stirring at rt the mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was washed with a mixture of ethyl acetate and n-heptane (50:50). Purification by silica gel column chromatography, eluting with 5% methanol in dichloromethane afforded the desired compound (126 mg, 43%). The compound was converted to the corresponding hydrochloride salt as described above.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:9][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1cc(O)nc(C)c1Br
Product: Cc1cc(OCCC(C)(C)O)nc(C)c1Br
Yield: 70.1 %

Procedure:
According to a method described in [WO 2009/054423 pamphlet, (Production Example 37)], from 5-bromo-4,6-dimethyl-2-hydroxypyridine (1.50 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (2.11 g), the subject compound (1.50 g) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])=[N:34][CH:33]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 38.3 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (18 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 19 mg of the title compound (38% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]#[N:31])=[CH:24][CH:23]=5)[C:13]4=[O:33])[CH2:11][O:10][C:9]3=[CH:34][C:5]=2[O:4][N:3]=1.O.[NH2:36][NH2:37]>C(O)C>[NH2:31][C:30]1[CH:29]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]4([C:8]5[C:9](=[CH:34][C:5]6[O:4][N:3]=[C:2]([CH3:1])[C:6]=6[CH:7]=5)[O:10][CH2:11]4)[C:13]3=[O:33])=[CH:27][CH:26]=2)[NH:37][N:36]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(-c3cc(N)n[nH]3)cc2)c2ccccc21
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 3-(4-((3-methyl-2′-oxo-6H-spiro[benzofuro[5,6-d]isoxazole-5,3′-indoline]-1′-yl)methyl)phenyl)-3-oxopropanenitrile in ethanol (20 mL) was added hydrazine hydrate (0.40 mL, 15 mmol). The solution was heated at reflux for 4 h, allowed to cool to ambient temperature and concentrated in vacuo. The resultant solid was dissolved in anhydrous methanol (10 mL) and a saturated solution of hydrogen chloride in anhydrous methanol (1.5 mL) was added, causing a precipitate to be deposited. The solid was collected by filtration to obtain 1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.14 g, 43%) as a pale yellow solid: mp 191-195° C. (methanol); 1H NMR (300 MHz, DMSO-d6) δ 7.82-7.71 (m, 3H), 7.52 (d, J=8.3 Hz, 2H), 7.31-7.18 (m, 2H), 7.10 (d, J=8.6 Hz, 1H), 7.04-6.97 (m, 2H), 6.40 (s, 1H), 5.16 (d, J=16.3 Hz, 1H), 5.05 (d, J=9.7 Hz, 1H), 4.98-4.89 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 164.3, 157.8, 155.9, 145.7, 142.7, 138.0, 130.5, 129.7, 128.3, 127.5, 126.6, 124.7, 124.4, 123.8, 117.8, 109.2, 108.5, 108.4, 81.5, 56.1, 43.5, 9.8; MS (ES+) m/z 463.9 (M+1). Anal. Calcd. for C27H21N5O3.1.6HCl: C, 62.15; H, 4.37; N, 13.42. Found: C, 61.97; H, 4.52; N, 13.15.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:48](=[O:57])([O:53][CH:54]([CH3:56])[CH3:55])[O:49][CH:50]([CH3:52])[CH3:51])P(=O)(OC(C)C)OC(C)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:37]/[P:48](=[O:57])([O:49][CH:50]([CH3:51])[CH3:52])[O:53][CH:54]([CH3:55])[CH3:56])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(OC(C)C)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), tetraisopropyl methylenediphosphonate (0.59 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diisopropyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.61 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:28]([O:30][CH3:31])=[O:29])(=[O:24])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:25]([S:22](=[O:23])(=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:26]=1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol) in DCM (2 mL) and pyridine (2 mL), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 350 mg of 3-[2-(benzo[b]thiophene-2-sulfonylamino)phenylsulfamoyl]-4-methoxybenzoic acid methyl ester. Tr 1.10 min, MS: 533.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 3.84 (s, 3H), 4.18 (s, 3H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 3H), 7.66 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.22 (dd, 1H), 8.34 (d, 1H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:32]([O:37][CH3:38])(=[O:36])[C:33]([CH3:35])=[CH2:34].O>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:34][CH:33]([CH3:35])[C:32]([O:37][CH3:38])=[O:36])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: C=C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C)CSc1cc(C)c(N)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
To a stirred solution of 1.00 g (5.1 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 0.15 g (0.5 mmol) of tetrabutylammonium fluoride in 5 mL of toluene at -5° C. is added dropwise a solution of 0.51 g (5.1 mmol) of methyl methacrylate in 5 mL of toluene. The reaction mixture is stirred for 24 hours at room temperature. The reaction mixture is then poured into 50 mL of water. The phases are separated and the organic phase is dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is purified by flash column chromatography (silica gel, 4:1, heptane:ethyl acetate eluent) to give 0.28 g (18%) of the title compound as a colorless liquid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:47])CC2C=CC=C(OC)C=2)[CH:6]=1.NCCCOC1C=C(OC)C=CC=1C(NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.[CH3:84][O:85][C:86]1[CH:87]=[C:88]([CH:91]=[CH:92][CH:93]=1)[CH:89]=O>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:47][CH2:89][C:88]2[CH:91]=[CH:92][CH:93]=[C:86]([O:85][CH3:84])[CH:87]=2)[CH:6]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCC(N)Cc2cccc(OC)c2)cc1
Reactant: COc1cccc(C=O)c1
Agent: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCNCc2cccc(OC)c2)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(3-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (26 mg, 0.042 mmol, 28%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 3-methoxybenzaldehyde.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[F:11]>CO>[Cl:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([NH2:8])=[C:9]([I:1])[CH:10]=1
Reactant: ClI
Reactant: Nc1ccc(Cl)c(F)c1
Solvent: CO
Product: Nc1cc(F)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Iodine chloride (20.6 ml, 1M solution in DCM, 20.6 mmol) was added dropwise to a solution of 4-chloro-3-fluoroaniline (2 g, 13.7 mmol) in methanol (35 ml) at 0° C. and the reaction mixture was stirred for 1 h at room temperature. Volatiles were removed under reduced pressure, water was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with water, dried with Na2SO4 and evaporated. The remaining residue was purified by chromatography with three consecutive columns (silica gel, heptane/EtOAc 98:2-93:7 and twice heptane/EtOAc 98:2-95:5) to obtain the title compound (2.51 g, 67%) as dark red solid. MS (ESI): 272.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:24][CH:21]2[CH2:23][CH2:22]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Hydroxy-4-nitro-benzoic acid methyl ester (10.5 g) was dissolved in dry DMF (150 ml) under N2 atmosphere. K2CO3 (24.3 g), K1 (2.6 g) and cyclopropylmethylbromide (10.3 ml) were added and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was diluted with water (300 ml) and extracted with Et2O (2×200 ml); the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation to yield 12.7 g of the desired intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.OS(O)(=O)=O.[CH3:17][CH2:18]O>>[CH2:17]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:18]
Reactant: Cc1cc(C(=O)O)cnc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(Cl)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 6-chloro-5-methyl-nicotinic acid (13.85 g, 80.75 mmol) in dry EtOH (200 mL) containing some drops of concentrated H2SO4 is stirred at reflux for 2 days. The solution is cooled to rt, the solvent evaporated, the residue dissolved in EA (200 mL) and washed with a solution of sat. aq. Na2CO3 (2×80 mL), 1M aq. KHSO4 (2×80 mL) and brine (50 mL). The org. phase is dried over MgSO4, filtered and evaporated to give 6-chloro-5-methyl-nicotinic acid ethyl ester (12.65 g) as a solid; LC-MS: tR=0.92 min; [M+1]+=200.10; 1H NMR (CDCl3) δ 1.43 (t, J=7.0 Hz, 3H), 2.46 (s, 3H), 4.43 (q, J=7.3 Hz, 2H), 8.16 (m, 1H), 8.84 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[N:11]([CH3:19])[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([N:16]([CH3:17])[CH3:18])[N:11]([CH3:19])[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: CN(C)c1nc(=O)n(-c2cc(O)c(Cl)cc2F)c(=O)n1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2c(=O)nc(N(C)C)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2.80 g (8.90 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H) -dione in 50 mL of acetone was added 1.47 g (10.7 mmol) of potassium carbonate and 1.98 mL (17.8 mmol) of an 80% solution of propargyl bromide in toluene. It was then warmed to reflux for 2 h. It was cooled to room temperature and the mixture was filtered and washed with excess ethyl acetate. The crude product was flash chromatographed over silica gel, eluting with a 3:7 v:v mixture of ethyl acetate and hexane to give 3.1 g of the title compound as a pale yellow solid, m.p.: 61°-65° C.; 1H-NMR (CDCl3, 200 MHz) ppm 7.0 (d, 1H), 4.75 (m, 2H), 3.45 (s, 3H), 3.1 (s, 6H), 2.6 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([CH2:29][C@H:30]1[O:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:31][C@H:30]([OH:32])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(NCc1ccccc1)CCCC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCCC2
Reaction time: 3 h
Yield: 66.2 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amine (187 mg) and (2S)-1-phenoxy-2,3-epoxypropane (100 mg) in dichloromethane (10 ml) was added yetterbium(III) trifluoromethanesulfonate (50 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amino]-3-phenoxy-2-propanol (190 mg).