Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.Cl>O1CCOCC1>[F:1][C:2]1([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: FC1(c2nccs2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(F)(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of the product of Example 27B (3.55 g, 14.59 mmol) in dioxane (40 mL) was added 1M HCl (100 mL). The reaction mixture was stirred overnight at ambient temperature, quenched with 10M NaOH (10 mL) and extracted with three portions of 1:1 ethyl acetate-hexanes. The combined organic layers were concentrated. The resulting residue was chromatographed on silica gel eluting with 0%-20% ethyl acetate-hexane to obtain the title compound (2.15 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82-7.95 (m, 2 H), 2.61-2.72 (m, 6 H), 2.24-2.42 (m, 2 H). MS (DCI) m/z 200 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:6].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CC(=O)CC>C(=O)(O)[O-].[K+].C(Cl)Cl>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:19][CH3:20])[CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:6])[CH2:16][CH2:15]2
Reactant: C1CCNCC1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCCl)CC2
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCN1CCCCC1)CC2
Temperature: 65 °C

Procedure:
A mixture of 3.0 parts of the N-(2-chloroethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide prepared in Example 8 and 4.3 parts of piperidine in approximately 40 parts of 2-butanone is heated at 65°C. for 20 hours. The reaction mixture is then stripped in vacuo and the residue taken up in dilute aqueous potassium bicarbonate solution and methylene chloride. The organic layer is dried and stripped in vacuo and the residue is crystallized from ether to afford 6,7-dimethoxy-1-phenyl-N-(2-piperidinoethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 101°-102°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1>>[C:32]([O:31][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:18][CH:19]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Product: COC(=O)c1ccc2c(c1)cc(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 2, Example 38, using the methyl 2-methyl-1H-indole-5-carboxylate instead of the methyl 1H-indole-5-carboxylate, and the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate instead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 456 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15].Cl.[NH2:18][OH:19]>C(O)C>[OH:19][NH:18][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH3:7])=[O:16])=[NH:15]
Reactant: COC(=O)CCCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)CCCCC(=N)NO
Yield: 86.9 %

Procedure:
Add sodium carbonate (4.5 g, 42 mmol) to a solution of commercially available 5-cyano-pentanoic acid methyl ester (5.0 g, 35 mmol) and hydroxylamine hydrochloride (2.9 g, 42 mmol) in ethanol (100 mL) at room temperature under nitrogen and heat the mixture at reflux for 5.5 h. Filter the mixture through celite and remove the solvent under reduced pressure to provide crude methyl 5-(N-hydroxycarbamimidoyl)pentanoate (5.3 g, 87% yield), which is carried forward without further purification.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.O.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)CCC>[N+:12]([C:11]1[C:2]2[NH:19][CH2:16][CH2:17][NH:18][C:4](=[O:6])[C:3]=2[CH:8]=[CH:9][CH:10]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NCCN
Solvent: O
Solvent: CCCCO
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 11.7 parts of methyl 2-bromo-3-nitrobenzoate, 8.1 parts of 1,2-ethanediamine monohydrate and 40 parts of 1-butanol was stirred for 1/2 hour at reflux temperature. The reaction mixture was evaporated and the residue was diluted with 50 parts of water. The precipitate was filtered off and washed with water and 2-propanol. It was then recrystallized from 2-methoxyethanol, yielding 6.5 parts of 2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodiazepin-5-one; mp. 191°-195° C. (interm. 1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccccc1Sc1ccc(Br)cc1
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: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccccc3Cl)cc2)c1C
Yield: 20.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(2-chlorophenylsulfanyl)-benzene (0.165 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.051 g, 20%) as a solid. MS calcd. for C26H21Cl2O2S [(M+H)+] 467, obsd. 467.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(Sc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
The above-mentioned ethyl 4-(4-chlorophenylthio)-3-nitrobenzoate (760 mg, 2.25 mmol) was dissolved in a mixture of ethanol (5 mL) and THF (10 mL). After addition of 2M aqueous sodium hydroxide (2.25 mL, 4.50 mmol), the mixture was stirred at room temperature for 4 hours and placed under reduced pressure to distill the solvent off. To the residue were added water (20 mL) and 2M aqueous hydrochloric acid until the mixture reached pH 2. The precipitated crystalline product was collected by filtration, washed successively with water (5 mL×3), a mixture (5 mL) of ethanol and water (1/4) and hexane (5 mL×2), and dried at 40° C. under reduced pressure, to obtain 703 mg (yield 100%) of the titled compound as a yellow crystalline product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][Cl:10])=[N:6][N:7]=1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1>[CH3:13][NH:14][C:15]([N:2]([CH3:1])[C:3]1[S:4][C:5]([C:8]([CH3:11])([CH3:12])[CH2:9][Cl:10])=[N:6][N:7]=1)=[O:16]
Reactant: CN=C=O
Reactant: CNc1nnc(C(C)(C)CCl)s1
Solvent: c1ccccc1
Product: CNC(=O)N(C)c1nnc(C(C)(C)CCl)s1

Procedure:
To a stirred suspension of 6.0 g of 2-methylamino-5-(β-chloro-α,α-dimethylethyl)-1,3,4-thiadiazole in 100 ml of benzene was added 2.0 g of methyl isocyanate. The mixture became homogenous upon heating to reflux temperature and reflux was maintained for 2 hrs. After cooling, the benzene was removed at reduced pressure and the precipitate collected, giving 7.4 g (95%), m.p. 159°-161°. An analytical sample was prepared from methylene chloride-ether, m.p. 160°-161°.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl.[CH2:10]([O:12][C:13](=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)[CH3:11].C([BH3-])#N.[Na+]>CO>[ClH:22].[CH2:10]([O:12][C:13]([C:14]1[N:6]([CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:16]=1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18]2)=[O:31])[CH3:11]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g. of 2-diethylaminoethylamine in 10 ml. of methanol is treated with 2 ml. of 5-N methanolic hydrochloric acid. Then, there are added successively under argon at 20°-25° C. a solution of 1.6 g. of o-benzoyl-p-chlorophenylglyoxylic acid ethyl ester in 5 ml. of methanol and 0.2 g. of sodium cyanoborohydride and the mixture is stirred for an additional 7 hours at room temperature. While cooling with ice, the mixture is made acidic with concentrated hydrochloric acid, stirred for an additional 0.5 hour at room temperature and evaporated to dryness under reduced pressure. The residue is made alkaline with 1-N sodium hydroxide with addition of ice and extracted with 50 ml. of ether. The ethereal extract is treated with 20 ml. of 0.5-N hydrochloric acid, and the mixture shaken thoroughly. After cooling in an ice-bath, the crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 1, and there is obtained 5-chloro-2-[ 2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN3CCCCC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.4 ml; 2.88 mmol; 6 eq) and 2-piperidin-1-yl-ethylamine (0.16 ml; 1.16 mmol; 2.4 eq) are added successively and the reaction mixture is stirred at 0° C. for 2 hours. The mixture is washed with water, NaHCO3 and dried over MgSO4, affording the title compound (170 mg; 68%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (21.1 g) and tetrabutylammonium hydrogen sulfate (1.5 g) in toluene (160 mL) −50% sodium hydroxide (160 mL) was added dropwise tert-butyl bromoacetate (20 mL) at 50° C., and the mixture was stirred at 50° C. for 1.5 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and then neutralized with 6M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an amorphous pale-yellow solid (24.4 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>O1CCCC1>[CH2:21]([NH:24][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Br:1])[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)c1cc([N+](=O)[O-])ccc1Br

Procedure:
To a solution of 2.5 g (0.01 mol) of 2-bromo-5-nitro-benzoic acid in 70 ml tetrahydrofuran are added dropwise 3.2 g (0.01 mol) of O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium-tetrafluoroborate, 5 ml triethylamine and a solution of 570 mg (0.01 mol) of allylamine in 5 ml tetrahydrofuran. After 60 minutes at ambient temperature the mixture is poured onto ice water, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>C(N(CC)CC)C.CN(C)C=O.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:22][C:21]=3[O:27][CH2:28][CH3:29])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(I)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C#CC(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Temperature: 50 °C
Yield: 83.7 %

Procedure:
4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-4-iodophenyl)-4,5-dihydro-1H-imidazole (566 mg, 1.05 mmol, example 27), copper(I) iodide (9.5 mg, 0.11 mmol), dichlorobis(triphenylphosphine)-palladium(II) (148 mg, 0.211 mmol) and 3,3-dimethyl-1-butyne (0.182 mL, 1.48 mmol) were dissolved under nitrogen in a flame-dried Schlenk tube in a mixture of triethylamine (1.7 mL) and dimethylformamide (1.7 mL). The reaction mixture was warmed in a 50° C. oil bath for 20 h, allowed to cool to room temperature and then partitioned between 2% sodium carbonate solution (70 mL) and diethyl ether (2×100 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluting with 1% methanol in methylene chloride) to give 4,5-bis-(4-chlorophenyl)-2-[4-(3,3-dimethylbut-1-ynyl)-2-ethoxyphenyl]-4,5-dihydro-1H-imidazole as an off-white foam (0.432 g, 83%). LC-MS: 491.3 [(M+H)+].
Reaction SMILES: [S:1]([C:5]1[S:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.[OH-:16].[Na+]>O>[S:1]([C:5]1[S:13][C:12]2[CH:11]=[CH:10][NH:9][C:8](=[O:16])[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(Cl)nccc2s1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc2c(=O)[nH]ccc2s1
Temperature: 100 °C
Yield: 66 %

Procedure:
A solution of 2-sulfamoyl-4-chlorothieno[3,2-c]pyridine (0.87 g, 3.5 mmol) in 10 N sodium hydroxide (1.8 ml) diluted with water (7 ml) was heated at 100° C. for 5-10 hours. After cooling the reaction and acidification with concentrated hydrochloric acid, the precipitated product was collected by filtration. Recrystallization from hot dimethyl sulfoxide by dilution with ethanol gives 0.53 g (66% yield) of product; m.p. 299°-301° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:65][C:66](O)([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68]>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][O:27][C:66]([CH3:65])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCOC(C)(C(F)(F)F)C(F)(F)F)CC4)cc3)oc12
Reaction time: 0.17 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}benzamide (50 mg, 0.112 mmol, EXAMPLE 43, Step A) and 1,1′-(azodicarbonyl)dipiperidine (57 mg, 0.226 mmol) in toluene (2 ml) was added tri-n-butylphosphine (0.06 ml, 0.241 mmol). After stirring for 10 min, hexafluoro-2-methylisopropanol (0.03 ml, 0.245 mmol) was added. Tetrahydrofuran (2 ml) was added to solubilize starting material, and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (8.7 mg, 0.014 mmol, 12.72% yield). Mass spectrum (ESI) 610.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.94 (d, J=8.5 Hz, 2H), 7.94 (d, J=1.5 Hz, 1H); 7.51 (s, 1H), 6.27 (br s, 1H), 3.72 (t, J=6.5 Hz, 2H), 3.46 (septet, J=6.5 Hz, 1H), 3.36 (t, J=6.0 Hz, 2H), 1.83 (m, 4H), 1.50-1.65 (m, 5H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.50 (m, 2H), 0.85-1.22, (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:21]([NH:28][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc(-c2cccc3ccccc23)c(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1c(CNCc2ccccc2)ccc(-c2cccc3ccccc23)c1Cl
Reaction time: 2 h

Procedure:
A solution of Example 5B (65 mg, 0.22 mmol) and benzylamine (0.024 mL, 0.22 mmol) in 1,2-dichloroethane (3 mL) at room temperature was treated with acetic acid (0.05 mL, 0.84 mmol), stirred for 2 hours, treated with sodium triacetoxyborohydride (64 mg, 0.31 mmol), stirred for 16 hours, and treated with saturated NaHCO3. The organic layer was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to ethyl acetate to provide the desired product. MS (ESI(+)) m/z 393 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ7.92 (d, 2H), 7.56-7.46 (m, 3H), 7.45-7.26 (m, 9H), 4.05 (s, 2H), 3.93 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:17]=1)=[N:10][CH:11]=2.[CH3:40][S:41]([CH2:44][CH2:45]Br)(=[O:43])=[O:42]>>[CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:45][CH2:44][S:41]([CH3:40])(=[O:43])=[O:42])[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[C:22]([F:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:17]=1)=[N:10][CH:11]=2
Reactant: CS(=O)(=O)CCBr
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)nc32)c(OC)c1
Product: COc1ccc(Cn2c(=O)n(CCS(C)(=O)=O)c3cnc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)nc32)c(OC)c1

Procedure:
300 mg (0.567 mmol) of the compound from example 93A were reacted in analogy to the method in example 83A with 2-bromoethyl methyl sulfone. 490 mg (100% of theory, 73% purity) of the title compound were obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:10](Cl)(=O)[CH:11]=[CH2:12]>CC(C)=O>[C:1]1([O:7][CH2:12][CH:11]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a reaction vessel equipped with a stirrer, thermometer, and reflux condenser 94 g (1.0 mol) of phenol, 40 g (1.0 mol) of NaOH, and 210 g of acetone were introduced. With stirring the contents, the internal temperature was elevated to 40° C. Subsequently, 76 g (1.0 mol) of acryloyl chloride was added dropwise thereto over 1 hour. After completion of the dropwise addition, the reaction mixture was further kept at 40° C. for 2 hours and reacted thereby. The reaction product was filtered to remove the NaCl yielded as a by-product, and the acetone was thereafter removed under reduced pressure to obtain 134 g of allyl phenyl ether.