Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.C([O-])(=O)C.[K+].[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1>C(#N)C.CCOC(C)=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>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(-c2cn3c(n2)-c2cc(-c4cnn(C)c4)ccc2OCC3)n(C(C)C)n1
Temperature: 150 °C
Yield: 82.3 %

Procedure:
A microwave vial was charged with a suspension of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.160 mg, 0.412 mmol) in 0.861 ml ACN/0.400 mL water. To this suspension was added potassium acetate (182 mg, 0.00185 mol) and 1-methylpyrazole boronic acid pinacol ester (107 mg, 515 mmol). The reaction suspension was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 132 mg of 454 (55% theoretical yield). MS: (ESI+)=390.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[NH:34]([C:38]1[S:39][CH:40]=[C:41]([CH2:43][S:44][CH2:45][CH2:46][NH2:47])[N:42]=1)[C:35]([NH2:37])=[NH:36]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:22]([NH:47][CH2:46][CH2:45][S:44][CH2:43][C:41]2[N:42]=[C:38]([NH:34][C:35]([NH2:37])=[NH:36])[S:39][CH:40]=2)=[O:23])[CH3:15])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.9 g (2.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.75 g (3.2 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=561 ([M+H]+, 3), 155 (26), 230 (100); IR (KBr): 1650 cm+1 (C=O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 140° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11](O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C1C=CC(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:30]([C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]1=2)=[N+:31]=[N-:32]
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)CCC[C@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a 500 mL three-neck round-bottomed flask equipped with argon inlet/outlet, thermometer, and magnetic stirring was added 5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (29 g, 140 mmol) in 280 mL of toluene. The reaction mixture was cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol, Aldrich) was added (internal temp.=−4° C.). DBU (25 mL, 170 mmol, Aldrich) was added over 10 min at such a rate that the internal temperature was kept below 1° C. The ice in the bath was allowed to melt, and the reaction continued for 12 h during which time the mixture stopped stirring because a precipitate had formed. Stirring was resumed, and the reaction mixture was stirred at RT for another 11 h. The reaction contents were poured into a 2 L sep funnel, and the lower dark-brown layer was removed. Water (250 mL) was added to the remaining top layer, and the mixture was extracted with Et2O (3×250 mL). The combined organic layers were washed with 1 M H3PO4, water, satd NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (330 g Isco Redisep® column, 1:1 hexane-CH2Cl2) of the crude material provided the title compound. MS (+ion ESI) m/z=232 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[NH2:18][C:4]1[N:3]=[C:2]([NH:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(N)cc1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C#N)cc2)nc(N)n1
Yield: 74 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-amino-benzonitrile provided the title compound (74% yield). 1H NMR (DMSO-d6) δ 1.41 (t, 3H, J=6.9 Hz, CH3), 4.15 (q, 2H, J=7.0 Hz, CH2), 6.53 (s, 2H, NH2), 6.84 (s, 1H, Ar), 7.17 (d, 1H, J-8.9 Hz, Ar), 7.43 (dd, 1H, J=8.8, 2.9 Hz, Ar), 7.71 (d, 2H, J=8.9 Hz, Ar), 7.92 (d, 1H, J=2.9 Hz, Ar), 8.00 (d, 2H, J=8.9 Hz, Ar), 9.70 (s, 1H, NH).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][CH3:29])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][CH3:29])[CH:10]=1
Reactant: CNS(=O)(=O)c1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 2.2 %

Procedure:
(Step 2) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g), 2-(aminomethyl)-4-chloro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (0.81 g) and potassium carbonate (0.88 g) were stirred in ethanol (10 ml) overnight at 70° C. The reaction solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3->1:0). 4N Hydrochloride-ethyl acetate solution (1 ml) was added to the obtained yellow oil, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (10 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][N:5]([CH:7]([F:9])[F:8])[CH:6]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH:7]([F:9])[F:8])[N:4]=1)=[O:12]
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 22° C. with N,O-dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HCl (154 mg, 0.8 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (2:1) to give the title compound (164 mg) as a colorless oil. MS: m/z=240.1 [M]+.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:19]2[CH:18]=[CH:17][C:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
To a solution of 6.60 g (0.0330 mole) of N,N-dimethyl-4-hydroxybenzenesulfonamide dissolved in 150 ml of DMSO was added 1.32 g (0.0330 mole) of NaOH. The mixture was heated at 60° C. for 10 minutes and 7.1 g (0.030 mole) of 4-fluorophenyl phenyl sulfone was added. The reaction mixture was heated at 100° C. for 3 hrs and at 125° C. for 3 hrs and cooled. The mixture was poured into a solution of 200 ml of 20% aqueous NaOH and 500 ml of water. The crystalline product was collected, washed well with water and dried, which gave 11.5 g (92% yield) of product. Recrystallization from aqueous DMSO followed by recrystallization from ethanol afforded purified N,N-dimethyl-4-(4-(phenylsulfonyl)phenoxy)benzenesulfonamide, mp 99°-100° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[S:37]([N:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[C:21]([Cl:43])=[CH:20][N:19]=1>>[Cl:43][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[S:37]([N:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CN(C)S(=O)(=O)c1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4S(=O)(=O)N(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-5-morpholin-4-yl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a light brown foam (0.043 g, 30%). MP: 74-85° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.96 (s, 1H), 8.29 (d, J=9.1 Hz, 1H), 8.07 (s, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.22 (dd, J=8.0 Hz and J=2.1 Hz, 1H), 7.10 (dd, J=9.2 Hz and J=2.9 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.88 (s, 1H), 3.92-3.88 (m, 4H), 3.54 (t, J=5.6 Hz, 2H), 3.36 (s, 3H), 3.22-3.18 (m, 4H), 2.93-2.83 (m, 4H), 2.78-2.68 (m, 12H). MS: 616.18 (MH)+.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=2)(C(OCC=C)=O)[C:22]([O:24]CC=C)=[O:23])=[CH:15][CH:14]=1)#[N:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([CH:21]([CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=1)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=1)([OH:24])=[O:23]
Reactant: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ccc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 41.8 ml (0.3 mol) of triethylamine and 8.6 ml (0.23 mol) of formic acid in 500 ml of dioxane is added to a solution of 43.5 g (0.09 mol) of diallyl 2-[2-(4-cyanophenyl)ethyl]-2-(4-methoxycarbonylbenzyl)malonate from Example 13A, 1.67 g (0.01 mol) of triphenylphosphine and 410 mg of palladium acetate in 505 ml of dioxane at room temperature. The reaction mixture is then stirred at 100° C. for 2 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 50:1). 25 g (0.074 mol, 82% yield) of a colorless solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][NH:17][CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:15][O:16][N:17]([CH3:18])[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: CNOC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6-bromo-naphthalene-2-carboxylic acid (0.6 g, 2.4 mmol) and O,N-dimethyl-hydroxylamine (0.28 g, 2.87 mmol) in CH2Cl2 (20 mL), was added EDC (0.55 g, 2.87 mmol), HOBt (0.39 g, 2.87 mmol) and TEA (0.66 mL, 4.8 mmol). The reaction was stirred at RT overnight. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography with (20-40% EtOAc/hexane) to give the titled compound as a white solid. MS (ESI, pos. ion) m/z: 294.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].Cl.[CH3:10]O>>[CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CC(C)(CO)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)(C)CO
Reaction time: 8 h

Procedure:
A mixture of 2,2-dimethyl-3-hydroxypropionic acid (CXXXII, 11.54 g, 97.7 mmol), methanol (150 ml) and methanol (25 mi) saturated with hydrochloric acid gas is stirred overnight at 20-25°. The mixture is then concentrated under reduced pressure, ether is added, and again the mixture is concentrated. The residue is dissolved in ether and poured cautiously into a small amount of saturated sodium bicarbonate. The phases are separated and the aqueous phase is washed several times with ether. The combined organic phases are backwashed with saline, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 2,2-dimethyl-3-hydroxypropionate (CXXXII), NMR (CDCl3) 1.20, 2.48, 3.56 and 3.71 δ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Yield: 33.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (187 mg, 0.696 mmol), 4-(4-phenyl-1,3-thiazol-2-yl)piperidine (170 mg, 0.696 mmol), diisopropylethylamine (0.121 ml, 0.696 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (84.0 mg, 33.1%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:25][C:26]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=2[CH:28]=1)[C:20]([O:22][CH3:23])=[O:21].ClC1C=CC2SC(CC(O)=O)=CC=2C=1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:25][C:26]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=3[CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cc2cc(Cl)ccc2s1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: O=C(O)Cc1cc2cc(Cl)ccc2s1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2cc(Cl)ccc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(5-chlorobenzothiophen-2-yl)acetate (prepared from 5-chlorobenzothiophene-2-acetic acid [CAS No. 23799-65-7] using General Procedure G, followed by amination using a procedure essentially the same as that described in Example D4 above), the title compound was prepared as a solid (mp=189-190° C.). The product was purified by titration using Et20/hexanes.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19]1>C(O)CC>[CH2:1]([NH:4][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:23]1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: Clc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Solvent: CCCO
Product: CCCNc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Yield: 74 %

Procedure:
50 ml of n-propylamine are added to a solution of 11.6 g (0.03 mole) of 6-chloro-9-[3-(4-phenoxymethylpiperidino)-propyl]-purine in 100 ml of n-propanol and the reaction mixture is heated under reflux for 6 hours. It is then evaporated in a vacuum and the residue extracted with diethyl ether. After evaporation of the solvent and recrystallization of the residue from cyclohexane, there are obtained 9.1 g of N6 -n-propyl-9-[3-(4-phenoxymethylpiperidino)-propyl]-adenine (74% of theory); m.p. 62° - 63° C.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl.O>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][CH2:29][C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1
Yield: 74.5 %

Procedure:
A solution of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-tert-butoxycarbonylaminobenzothiazol-6-yl ester (intermediate 81) (170 mg, 0.344 mmol) and trifluoroacetic acid (14.9 g, 130.7 mmol) in 10 ml of dichloromethane and 100 μl of water is stirred for 2 hours at room temperature. The reaction medium is evaporated to dryness, taken up in ethyl acetate and washed with water, and then with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated to dryness to give 130 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester; compound with trifluoroacetic acid in a yield of 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([NH:30][CH3:31])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [C:1]([O-])(=[O:3])C.[NH4+].[NH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]>C(O)=O>[CH:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])=[O:3]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1sccc1N
Agent: [NH4+]
Solvent: O=CO
Product: COC(=O)c1sccc1NC=O
Yield: 98.5 %

Procedure:
Formic acid 125 ml, and ammonium acetate (15.9 g, 207 mmol) were added to methyl 3-amino-2-thiophene carboxylate (25 g, 159.04 mmol) and the mixture was refluxed for 4 hours. After lowering the temperature to room temperature, the synthesized solid was washed with water and the title compound (29 g, 98%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])=[CH:5][C:4]=1[F:22])#[CH:2].[N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N+:24]=[N-:25].N1C(C)=CC=CC=1C>C(#N)C.[Cu](I)I>[CH2:26]([N:23]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][N:15]4[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]4)[O:11][C:10]3=[O:21])=[CH:5][C:4]=2[F:22])[N:25]=[N:24]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccc(N2C[C@H](Cn3cc(C)nn3)OC2=O)cc1F
Agent: I[Cu]I
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4cn(Cc5ccccc5)nn4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Yield: 26 %

Procedure:
(5R)-3-(4-Ethynyl-3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 9, 40 mg, 0.133 mmol), azidomethyl-benzene(21.2 mg, 0.16 mmol), copper iodide (2.5 mg, 0.013 mmol) and 2,6-lutidine were mixed in dry acetonitrile (2 mL) and stirred at room temperature for over night. The reaction mixture was filtered through a 0.45 μm membrane, the filtrate was concentrated to an oil and purified by reverse phase chromatography with 5%˜95% MeCN in H2O (0.1% TFA). The product was obtained as a colourless solid (15 mg).