Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)#[CH:11]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:10]#[C:11][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#Cc1cccc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(C#Cc2nc(C)ccc2N)c1
Yield: 46.7 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted with (PPh3)2PdCl2 (37 mg, 0.05 mmol), Cul (10 mg, 0.05 mmol) and 1-ethynyl-3-methoxy-benzene (204 μl, 1.60 mmol) in triethylamine (5 ml) during 1.5 h. The crude residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to yield 118 mg (0.50 mmol, 46%) of (2-(3-methoxy-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[C:40]1(=[O:56])[N:44]([CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)[C:43](=[O:51])[C:42]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]12.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:47]4[CH2:48][CH2:49][CH2:50][C@@H:45]([N:44]5[C:43](=[O:51])[C:42]6=[CH:52][CH:53]=[CH:54][CH:55]=[C:41]6[C:40]5=[O:56])[CH2:46]4)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccccc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
10.00 kg (22.06 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 12.59 kg (33.09 mol) of 3-(phthalimido)piperidine D-tartrate and 17.5 liters of N-methyl-2-pyrrolidone are initially charged in the reactor. The reactor contents are heated to 140° C. After the temperature has been attained, 11.41 kg (88.24 mol) of diisopropylethylamine are metered in within 20 minutes. The feed vessel is flushed with 2.5 liters of N-methyl-2-pyrrolidone and the reaction mixture is subsequently stirred at 140° C. for 2 hours. After the reaction has ended, the reaction mixture is cooled to 60° C. and diluted with 80 liters of methanol. The resulting suspension is stirred at 50° C. for 30 minutes, then cooled to 23° C. and stirred for a further 30 minutes. Subsequently, the product is centrifuged off and washed 3 times with 20 liters each time of methanol. Drying is effected at 45° C. in a drying cabinet under inertization.
Reaction SMILES: [OH-].[K+].Cl[CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)[CH3:20]
Reactant: O=C(c1ccccc1)c1ccc(CCl)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOCc1ccc(C(=O)c2ccccc2)cc1
Yield: 84 %

Procedure:
To 1 liter of absolute ethyl alcohol was added 80 grams (1.2 moles) of 85% potassium hydroxide pellets with mechanical stirring. The amount of 115 grams (0.5 moles) of 4-(chloromethyl)benzophenone was added to the resulting warm solution. The reaction mixture was refluxed for three hours, filtered with suction, and concentrated. Water was added and the lower oily layer was separated and distilled to provide 102 grams (84% yield) of 4-(ethoxymethyl)benzophenone. Infrared analysis revealed the presence of a carbonyl band at 1660 cm-1. Ultraviolet analysis revealed λ max (ε) of 256 nanometers (18,360). Proton nuclear magnetic resonance analysis revealed the following where m is a multiplet, s is a singlet, q is a quartet, t is a triplet and TMS is tetramethylsilane.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:13][O:14][C:15]([CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[O:16].O>N1C=CC=CC=1.N1CCCCC1>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][C:15]([O:14][CH3:13])=[O:16])[CH:20]=1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Reactant: COC(=O)COc1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)[nH]c2=O)c1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
In a mixture of 9 ml of pyridine and 150 μl of piperidine were dissolved 0.75 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone and 0.75 g of 3-[(methoxycarbonyl)methoxy]benzaldehyde, and the solution was heated under reflux for 4 hours. After cooled to room temperature, 20 ml of water was added, precipitated crystals were filtered, washed with water, washed with tetrahydrofuran, and dried to obtain 0.42 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (7a)] as a yellow crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[N:22]12[CH2:32][CH2:31][CH2:30]N=C1CCCCC2.C1(N)CC1>C(O)C>[CH:32]1([NH:22][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]3)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)N1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: C1CCC2=NCCCN2CC1
Agent: NC1CC1
Solvent: CCO
Product: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2[N+](=O)[O-])CC1
Yield: 47.7 %

Procedure:
A solution of 126.0 g (0.4 mole) of 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylic acid, ethyl ester (prepared as described in European Patent Publication No. 9425), 76.1 g (0.5 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 28.6 g (0.5 mole) of cyclopropylamine and 500 ml of absolute ethanol was stirred at room temperature for 48 hours. The solution was then heated at reflux for four hours and concentrated in vacuo. The residue was partitioned between chloroform and water. The chloroform layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to give 64.0 g of the title compound, mp 100°-103° C.
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]2[C:37](=[O:62])[N:38]([CH2:48][C:49]([NH:51][CH:52]([CH:59]([CH3:61])[CH3:60])[C:53](=[O:58])[C:54]([F:57])([F:56])[F:55])=[O:50])[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:40][CH:41]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[C:2]([NH:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]2[C:37](=[O:62])[N:38]([CH2:48][C:49]([NH:51][CH:52]([CH:59]([CH3:60])[CH3:61])[C:53](=[O:58])[C:54]([F:56])([F:57])[F:55])=[O:50])[C:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:40][CH:41]=2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NS(=O)(=O)c2cccc(N)c2)c1=O)C(=O)C(F)(F)F
Product: CC(=O)Nc1cccc(S(=O)(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c2=O)c1

Procedure:
Using a procedure similar to that described in Example 197.1., except replacing trifluoroacetic anhydride with acetic anydride, 2-[3-(3-aminophenylsulfonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was converted into the title compound. Chromatography solvent: dichloromethane:methanol (35:1); TLC: Rf =0.24, dichloromethane:methanol (20:1); NMR (DMSO/D2O): 8.22 (s,1) 7.73 (d,1), 7.60 (d,1), 7.5 (br m, 7), 6.16 (d,1), 4.40 (m,2), 4.02 (d,1), 2.12 (m,1), 2.09 (s,3), 0.80 (d,2); MS: m/z=593(M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:7]2[N:8]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:39]=[N+:40]=[N-:41])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:41][N:40]=[N:39][N:34]=3)=[CH:25][CH:26]=2)[C:7]2[N:8]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2c(-c3ccccc3)c(C)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nn2c(-c3ccccc3)c(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 32 %

Procedure:
Following the procedure of Example 1, Step G, 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-methyl-6-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step B) was reacted with trimethyltin azide to give a 32% yield of the title compound as a brown solid, mp>108° C. (gradual); homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.Cl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 17, 0.35 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.25 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.3 g of desired product. MS (electrospray): 385 (M+1) for C17H16FN8O2.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:35]([CH3:36])=[C:34]([CH3:37])[C:33]([CH3:38])=[C:32]([CH3:39])[C:31]=1[CH3:40])(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:40])=[C:32]([CH3:39])[C:33]([CH3:38])=[C:34]([CH3:37])[C:35]=3[CH3:36])(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: Cc1c(C)c(C)c(S(=O)(=O)NCCN=[N+]=[N-])c(C)c1C
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: Cc1c(C)c(C)c(S(=O)(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)c(C)c1C

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.120 g, 0.434 mmol) was reacted with N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide (0.141 g, 0.434 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2,3,4,5,6-pentamethylphenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), δ 7.01 (s, 1H), δ 6.44 (s, 1H), δ 6.17 (s, 2H), δ 4.35 (s, 2H), δ 3.34 (s, 2H0, δ 2.47 (s, 2H), δ 2.48 (s, 6H), δ 2.20 (m, 1H), δ 1.43 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 149.6, 148.1, 139.7, 136.2, 134.9, 134.3, 122.4, 84.9, 53.7, 50.2, 42.5, 31.1, 29.3, 28.9, 28.4, 28.2, 25.6, 19.1, 17.9, 17.2 ppm; HRMS (ESI) calcd for C28H43N7O4S (M+) 573.3097, found 573.3086, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide hydrochloride (0.143 g, 76% yield). 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), δ 6.42 (s, 1H), δ 4.48 (s, 2H), δ 3.34 (s, 2H), δ 2.65 (s, 2H), δ 2.40 (s, 8H), δ 2.12 (s, 9H), δ 1.58 (s, 4H), δ 1.19 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 159.9, 147.3, 139.6, 136.1, 134.8, 134.0, 127.8, 127.6, 108.6, 108.4, 54.1, 51.5, 41.8, 36.5, 28.2, 28.1, 27.7, 24.1, 23.7, 18.2, 16.8, 16.1 ppm; HRMS (ESI) calcd for C23H35N7O2S (M+) 473.2573, found 473.2565.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9]([C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[NH:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[C:9]([C:13]1[CH:17]=[C:16]([C:18]([NH:8][CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:19])[NH:15][N:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NCCc1ccco1
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NCCc2ccco2)[nH]n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
2-(furan-2-yl)ethanamine (0.81 g, 7.30 mmol) was added to a premixed (10 min) solution of 3-tert-butyl-1H-pyrazole-5-carboxylic acid (0.61 g, 3.60 mmol), DCC (1.51 g, 7.30 mmol) and HOBt (0.99 g, 7.30 mmol) in DCM:DMF-solution (10 ml, 2:9, v/v). After stirring for 15 h at RT the reaction mixture was filtered through a pad of Celite and the filtrate was washed two times with water, evaporated to dryness and purified with CombiFlash to afford 0.36 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.27 (s, 9H), 2.84 (t, 2H), 3.46 (m, 2H), 6.17 (m, 1H), 6.35 (m, 2H), 7.52 (m, 1H), 8.08 (m, 1H), 12.89 (m, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35]>C(#N)C.C(Cl)Cl>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](/[N:7]=[C:5]1\[S:6][C:2](=[CH2:1])[CH2:3][N:4]\1[C:8]1[CH:21]=[CH:20][C:11]2[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=2[CH:9]=1)=[O:35]
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/C(=N/C(=O)CC(C)(C)C)S1
Temperature: 65 °C

Procedure:
To a solution of 5-methylene-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazolidin-2-imine (Example 22C, 0.14 g, 0.44 mmol) in acetonitrile (3 mL) was added Hunig's base (0.062 g, 0.48 mmol) followed by 3,3-dimethylbutanoyl chloride (0.088 g, 0.66 mmol). The mixture was heated for 12 hours at 65° C. The reaction mixture was cooled down, diluted with CH2Cl2 (50 mL), and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure, the residue was chromatographed over silica using CH2Cl2-5% MeOH/CH2Cl2 to supply the titled compound. 1H NMR (CDCl3) δ ppm 1.00 (9 H), 2.35 (2 H), 4.65 (2 H), 5.25 (1 H), 5.35 (1 H), 7.15 (1 H), 7.25 (1 H), 7.55 (1 H); MS (ESI) m/z 419(M+H)+.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc([C@@H]2C[C@H]2NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and pyridine-2-carbaldehyde (0.17 mL, 1.80 mmol) in CH2Cl2 (12 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.48 g, 2.25 mmol) was slowly added and stirring continued for 2 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel [4% MeOH+1% NH3 (aq)/CH2Cl2] followed by preparative layer chromatography (5% MeOH/CH2Cl2) affording 0.08 g of N-[(trans)-2-phenylcyclopropyl]-N-(pyridin-2-ylmethyl)amine [Rf=0.3 (5% MeOH/CH2Cl2), colorless oil, 24% yield]. 1H-NMR (CDCl3, 250 MHz, δ): 8.60-8.54 (m, 1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H, ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m, 1H, CH2).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:28])[NH:22]2>>[Cl:27][C:26]1[C:18]([CH3:17])=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:28])[C:20]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.4 g of 5-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8](Cl)[C:7]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].[OH2:23]>>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:23])[C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: O
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1O
Yield: 53.3 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, (N-tetrahydroisoxazyl)-2,6 -dichloro-3-nitrobenzenesulfonamide (0.1 g, 0.29 mmol), 80% NaH (26 mg, 0.88 mmol) and water (6.3 μL, 0.35 mmol) were reacted to form the desired product (50 mg, 53%). LC-MS m/z 323(M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1Br)C(c1ccccc1)=CC(C)(C)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)C=C(c2ccccc2)c2cc(Br)c(O)cc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-7-methoxy-2,2-dimethyl-4-phenyl-2H-chromene (Compound 52, 992 mg, 3.22 mmol) in dichloromethane (20 mL) under argon at 0° C. was added boron tribromide (1M in dichloromethane, 3.8 mL, 3.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with ice. The product was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo and purified by column chromatography (silica gel, 5% ethyl acetate in hexane) to produce the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[C:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:27][CH2:28]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a mixture of 2-chloro-4-(chloromethyl)pyridine (500 mg, 2.05 mmol) and K2CO3 (1.14 g, 4 equiv) in DMF (50 ml), was added N-Boc-piperazine (558 mg, 1.1 equiv.). The mixture was stirred at rt for 1 h, after which TLC showed that no starting materials remained. The DMF was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4, concentrated, and applied onto a silica gel column. The title compound (570 mg, yield 91%) was obtained as a colorless gel.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7](C2C=CC(O)=CC=2)C2C=CC(O)=CC=2)[C:4]([C:22]([OH:24])=O)=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O>[CH:22]1[O:24][CH:7]=[C:5]2[C:4]=1[CH:3]=[CH:2][CH:1]=[CH:6]2
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc2cocc2c1
Temperature: 0 °C

Procedure:
To a dry 250 mL round bottom flask equipped with a mechanical stirrer containing 20 g (0.062 mol) of phenolphthalin at 0° C. was added, with stirring, 25 mL of conc. sulfuric acid (cooled to 0° C.) This mixture was stirred slowly for 2-3 min. and poured into a 1L beaker containing 600 mL of ice-water. To retrieve the remaining solids there was added cold water (~20-30 mL×4) while a spatula was used to scrape out the remainder. The solids were combined. The green solid was then filtered, washed with 1 L of cold water and dried for 15-20 min. before being used in the Diels-Alder reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CCCOc1ccc(Cl)cc1Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of ethyl 4-(2,4-dichlorophenoxy)-butyrate (57 g, crude from last step, about 0.2 mol) in THF (500 mL) and water (500 mL) was added LiOH.H2O (12.6 g, 0.3 mol), and the reaction mixture was stirred for 5 h at RT. The mixture was washed with Et2O (3×200 mL), and the aqueous layer was acidified by addition of HCl (20%) to pH ˜2. The mixture was extracted with EtOAc (3×400 mL), the combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the butyric acid (37 g, 74.3% from 2,4-dichlorophenol) as a white solid. 1H-NMR (CDCl3): δ 7.36 (d, 1H, J=8.8 Hz), 7.18 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.84 (d, 1H, J=8.8 Hz), 4.07 t, 2H, J=7.2 Hz), 2.64 (t, 2H, J=7.2 Hz), 2.17 (p, 2H, J=6.4 Hz).