Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1S.S(Cl)(Cl)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:2]2[O:3][C:4]3[C:9]([N:1]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Sc1nc2cccnc2o1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cccnc3o2)CC1
Temperature: 60 °C
Yield: 19.1 %

Procedure:
To oxazolo[5,4-b]pyridine-2-thiol (1.0 g, 6.57 mmol, 1.0 equiv) was added thionyl chloride (14.1 g, 8.6 mL, 118.3 mmol, 18.0 equiv) and anhydrous DMF (0.56 g, 0.56 mL, 7.23 mmol, 1.1 equiv) and the reaction mixture heated to reflux for 30 min. The solvent was removed under reduced pressure and the crude oil azeotroped twice with xylene to remove excess thionyl chloride. To the crude reaction product was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 9.86 mmol, 1.5 equiv) in anhydrous DMF (5 mL) and the solution heated to 60° C. for 18 h. The solution was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/hexane (1:1) to give 0.40 g (19%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.34 (s, 9H), 1.26-1.40 (m, 2H), 1.84-1.92 (m, 2H), 2.82-2.95 (m, 2H), 3.67-3.76 (m, 1H), 3.82-3.84 (m, 2H), 7.13 (t, J=7.0 Hz, 1H), 7.52 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 7.79 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Br:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>ClCCl.C(OCC)(=O)C.O.N1C=CC=CC=1>[Br:31][C:32]1[CH:33]=[C:34]([NH:35][C:14]([C:12]2[S:13][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Reactant: Nc1cccc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)c1)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 351C was dissolved in dichloromethane followed by the addition of a solution of oxalyl chloride and a catalytic amount of dimethylformamide. The solution was stirred at room temperature for 3 hours followed by the addition of 3-bromoaniline and pyridine. The resultant solution was stirred at room temperature for 20 hours followed by the addition of water and extraction of the solution with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the crude product, which was purified by silica gel chromatograpy to provide the title product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:12][CH:11]2[CH2:13][CH2:14][CH2:15][C:9]3=[C:10]2[CH:4]([CH2:5][N:6]([O:16]C)[CH:7]=[CH:8]3)[CH2:3]1.B(Br)(Br)Br.CO>ClCCl>[CH3:1][CH:2]1[CH2:12][CH:11]2[CH2:13][CH2:14][CH2:15][C:9]3=[C:10]2[CH:4]([CH2:5][N:6]([OH:16])[CH:7]=[CH:8]3)[CH2:3]1
Reactant: CON1C=CC2=C3C(CCC2)CC(C)CC3C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC1CC2CCCC3=C2C(C1)CN(O)C=C3
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 2.31 g (10 mmol) of 2-methyl-5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine in 25 ml of dichloromethane was cooled to -70° C., and 20 ml of 1M boron tribromide in dichloromethane was added. The mixture was allowed to warm to room temperature and then cooled to -40° C., and then treated with 10 ml of methanol. Solvents were removed under reduced pressure and the residue was crystallized from methanol ether to afford 1.8 g (60%) of 2-methyl-5-hydroxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine (HBr salt, mp 217°-218° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](Cl)=[O:6].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:8]=[CH:9][N:10]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccnc(Cl)c1

Procedure:
To a solution of 4.2 g 2-chloro-isonicotinoyl chloride in 25 ml. fluorobenzene there is added with cooling 11.7 g AlCl3. The mixture is heated at 70°-80° C. during 7 hrs. The crude is added to acidic (pH 1-2) cold water. The pH is raised until 4.5 with diluted aqueous NaOH. This aqueous organic mixture is extracted several times with methylene chloride. The combined extracts are washed with water, dried (Na2SO4) and distilled in a rotary evaporator. The remaining crude oil is purified through a silica column, eluting with ethyl ether: petroleum ether 1:3. Yield 5 g of the title product, m.p. 60°-3° C. (cyclohexane); UV (ethanol) λmax.: 262 nm, ε=10,250; Cl 15.30 (15.05); F 8.15 (8.06).
Reaction SMILES: N([N:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4]1)=O.C([O-])(O)=O.[Na+].[C:18](O)(=O)[CH3:19]>[Zn]>[CH3:4][N:3]1[CH2:19][CH2:18][C:12]2[N:3]3[CH2:4][CH2:5][S:6][C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:8]3=4)[C:7]=2[CH2:8]1
Reactant: O=NN1CCSc2ccccc21
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Product: CN1CCc2c(c3cccc4c3n2CCS4)C1
Temperature: 95 °C

Procedure:
4-Nitroso-3,4-dihydro-2H-benzo[1,4]thiazine (1 g, 5.55 mmol) was dissolved in acetic acid (25 mL) and N-Me- piperidone (753 mg, 6.66 mmol) and zinc dust (1.8 g, 27.77 mmol) was added portionwise at RT. The reaction mixture was heated at 95° C. for 2 h. After completion of reaction, the mixture was basified with NaHCO3 and extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to obtain product. 1H NMR (CD3OD, Formate Salt): d (ppm): 7.20 (d, 1H), 6.98 (t, 1H), 6.90 (d, 1H), 4.32 (t, 2H), 4.28 (s, 2H), 3.50 (t, 2H), 3.30 (m, 2H), 3.10 (t, 2H), 2.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]2[N:20]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:19]2[N:24]=[CH:23][C:22]3=[CH:25][CH:26]=[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:21]3[N:20]=2)=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: COc1ccc(N)cc1N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccc(Nc2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)cc1N1CCOCC1
Yield: 38.7 %

Procedure:
4-Methoxy-3-morpholin-4-yl-phenylamine (80.0 mg, 0.384 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (70.0 mg, 0.192 mmol) and N,N-Diisopropylethylamine (0.100 mL, 0.576 mmol) were dissolved in 1-Methoxy-2-propanol (0.75 mL, 7.7 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced and the crude residue was isolated and purified by Gilson prep HPLC to afford 37.80 mg of N-{2-[2-(4-Methoxy-3-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=509.0. 1H NMR (400 MHz, DMSO, d6) δ 9.18 (s, 1H), 8.94 (s, 1H), 7.73 (m, 1H), 7.65 (m, 1H), 7.52 (m, 2H), 7.41 (m, 1H), 7.05 (d, 1H, J=8.80 Hz), 6.91 (m, 1H), 6.83 (m, 2H), 3.72 (s, 3H), 3.61 (m, 4H), 3.06 (s, 3H), 2.79 (s, 3H), 2.60 (m, 4H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([OH:20])=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[Si:9]([O:16][C@@H:17]([CH2:21][O:22][CH3:23])[C:18]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=1)=[O:20])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1ccc(N)nc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.55 mL, 11.7 mmol) in DCM (5 mL) was added dropwise to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid C4c (2.5 g, 10.7 mmol) in DCM (15 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 30 minutes. N-Ethyl-N-isopropylpropan-2-amine (2.74 mL, 16.0 mmol) was added in one portion followed by 5-methylpyridin-2-amine (CAS 1603-41-4) (1.27 g, 11.73 mmol) in DCM (5 mL) dropwise. The resulting solution was stirred at ambient temperature for 1 hour. 1M Citric acid (10 mL) was added and the mixture extracted with EtOAc (20 mL). The organic phase was washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered and evaporated to provide the crude product. Purification by flash silica chromatography, elution gradient 20 to 100% EtOAc in isohexane furnished (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (1.4 g). 1H NMR (400 MHz, CDCl3) δ 0.2 (6H, s), 1.01 (9H, s), 2.32 (3H, s), 3.41 (3H, s), 3.66-3.75 (2H, m), 4.40-4.42 (1H, m), 7.52 (1H, d), 7.14-7.16 (2H, m), 9.04 (1H, s), m/z (ESI+) (M+H)+=326; HPLC tR=2.75 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-phenylacetamide (0.052 g, 0.12 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.025 g, 0.17 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 50% dichloromethane in ethyl acetate and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.011 g, 17%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.23 (s, 2H, NCH2CO), 3.71 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=9.15 Hz, 2H, 3,5-C6H4NMe2 or 2,6-C6H4—NMe2), 7.06 (t, J=7.52 Hz, 1H, p-ArH), 7.32 (t, J=7.52 Hz, 2H, m-ArH), 7.68 (d, J=7.52 Hz, 2H, o-ArH), 8.02 (d, J=8.90 Hz, 2H, 3,5-C6H4NMe2 or 2,6-C6H4—NMe2), 8.16 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.82 (s, 1H, CONH), 13.20 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([Cl:25])[CH:17]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:33]3[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]3)=[O:22])=[C:18]([Cl:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCN1CCNCC1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(CC)CC3)c(Cl)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.27 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-chloro-benzoic acid (A-40) using 40 mg (0.40 mmoL) N-ethyl piperazine, 102 mg (0.53 mmol) EDC, 72 mg (0.53 mmol) HOBt and 68 mg (0.53 mmol) DIPEA in 1.2 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 67 mg (53%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([O:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])(=[O:14])=[O:13])(=[O:9])[CH3:8]>>[C:7]([O:10][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])(=[O:14])=[O:13])[C:2](=[O:3])[O:4][CH2:5][CH3:6])(=[O:9])[CH3:8]
Reactant: CC(=O)ONS(=O)(=O)c1ccccc1Br
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N(OC(C)=O)S(=O)(=O)c1ccccc1Br

Procedure:
Ethyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (49) is prepared from ethyl chloroformate and N-(acetyloxy)-2-bromobenzenesulfonamide according to Scheme 3. δH (250 MHz, CHLOROFORM-d) δ 8.23-8.37 (1H, m), 7.74-7.85 (1H, m), 7.45-7.60 (2H, m), 4.21 (2H, q, 7.2 Hz), 2.34 (3H, s), 1.19 (3H, t, 7.2 Hz).
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([OH:11])=[CH:8][CH:7]=[N:6]2.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][C:9]2[C:10]3[N:5]([CH:4]=[CH:3][N:2]=3)[N:6]=[CH:7][CH:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccnn2ccnc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccnn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of imidazo[1,2-b]pyridazin-8-ol hydrochloride (D-5) (4 g, 23.3 mmol, 1.0 eq) and triethylamine (7.1 g, 70.0 mmol, 3.0 eq) in DCM (50 mL), 4-toluenesulfonyl chloride (5.3 g, 28.0 mmol, 1.2 eq) is added in portions and the resulting mixture is stirred at RT for 1 h. The mixture is washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (10-50% ethyl acetate-petro ether) to afford the product, imidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate (D-6).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12]#N)[CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])C=1Cl.[H-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])[C:12]=1[CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCc1cnc2ccccc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1

Procedure:
3-(2,6-Dichloro-4-nitro-benzyl)-quinoline was synthesized (71%) from quinolin-3-yl-acetonitrile (228, 1.41 g, 8.4 mmol), 3,4,5-trichloronitrobenzene (Acros, 1.90 g, 8.4 mmol) and NaH (Aldrich, 740 mg, 60%, 18.5 mmol) in a similar manner in two steps as described in Example 222.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:6]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1)#[CH:5]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.07 g (12.4 mmol) of methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate are mixed, in a 500 ml three-necked flask, with 50 ml of THF, and 13.7 ml of a tetrabutylammonium fluoride solution (1 M /THF) are added dropwise. The reaction medium is stirred for 1 h at room temperature and is then poured into water and extracted with ethyl ether. After separation of the phases by settling, the organic phase is dried over magnesium sulphate and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([CH2:23][C:24]([OH:26])=[O:25])[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:12])=[O:11])=[N:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cn1
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide with tert-butyl bromoacetate
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.Cl.[CH:22]1([C:25]2[CH:26]=[C:27]([CH3:37])[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:29][CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[CH:26]=[C:27]([CH3:37])[C:28]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:35][CH2:36]3)=[N:29][CH:30]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 81.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (424 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].[C:30](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccc(O)cc2)C1c1ccccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(2-chlorophenyl)-3-(4-hydroxyphenyl)sulfonyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (4.33 g), potassium carbonate (2.76 g), methyl iodide (5.68 g), and N,N-dimethylformamide (DMF) (25 ml) was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was crystallized from ether to give 4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfonyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, m.p. 176°-178°.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:23][C:22]2=[O:33])[CH:9]=[CH:8][C:7]=1[Cl:34])C.[OH-].[Li+]>O1CCOCC1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][C:7]([Cl:34])=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[CH:11]=2)=[C:14]([CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:23][C:22]2=[O:33])[CH:15]=1
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(Br)ccc1Oc1ccc(Cl)c(CC(=O)O)c1

Procedure:
Hydrolysis of {5-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-2-chloro-phenyl}-acetic acid ethyl ester (0.32 mmol) in 1,4-dioxane with aqueous lithium hydroxide, followed by purification by preparative HPLC, gave the desired product.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[CH2:9]([N:16]1[C:5](=[O:6])[CH2:4][O:3][CH:2]([C:1]([OH:7])=[O:8])[CH:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1COCC(=O)O1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)C1OCC(=O)N(Cc2ccccc2)C1c1ccccc1
Temperature: 0 °C
Yield: 43 %

Procedure:
9.86 g (0.085 mole) of diglycolic anhydride and 16.5 g of Schiff base (0.085 mole), prepared from benzyldehyde and benzylamine, are refluxed at 140° C. in 220 ml of xylene for 6 hr. After cooling to 0° C. the solid is collected and washed with ether: 14.5 g (54%) mp 170°-9° C. Recrystallization from methylenechloride (little) and ether gave 11.3 g (43%) of title compound mp 177°-81° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00046 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.13 g, 0.0023 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.14 g, 0.00116 mol) was added and stirred for further 3 h. At 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.032 g, 20% yield). 8-Ethyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.032 g, 0.000095 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.000095 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.030 g, 75% yield).