Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([C:18](N(OC)C)=[O:19])=[N:16][S:17][C:13]=2[CH:12]=1.Cl>C1COCC1>[Br:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:19])=[N:16][S:17][C:13]=2[CH:12]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1nsc2cc(Br)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Chlorophenyl magnesium bromide (1.0 N in THF, 16 mL, 16 mmol) was added to a stirred solution of 6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (3.5 g, 12 mmol) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was poured into 1N HCl and extracted into ether. The combined organic layers were washed with brine, dried and concentrated. The crude product was suspended in ether and stirred for 15 minutes. The solid was collected by filtration to give (6-bromobenzo[d]isothiazol-3-yl)(4-chlorophenyl)methanone (3.3 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, J=8.8 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.19 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH2:27]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH2:28][C:29]#[CH:30].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.[Cu]I.CN(C=O)C>[O:41]=[C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[N:31]1[CH2:27][CH2:28][C:29]#[C:30][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#CCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 150 °C
Yield: 76.9 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.59 g), 2-(but-3-ynyl)isoindol-1,3-dione (0.3 g), dichlorobis(triphenyl phosphine)palladium (II)(53 mg), copper(I) iodide (29 mg), and triethylamine (0.39 ml) were added to DMF (4 ml). The mixture was heated at 150° C. (microwave reactor) for 10 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40→30:70). The purified product was condensed under reduced pressure to give the title compound (0.51 g) as a yellowish-white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>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.O>[N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[C:18][C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2cnc3ccccc3c2)CC1
Yield: 655.7 %

Procedure:
A well homogenised mixture of the Compound 1c (50 mg, 0.21 mmol), 3-bromoquinoline (0.039 ml, 0.21 mmol), bis-(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol) and tetra-butylammonium fluoride (215 mg, 0.82 mmol) was stirred at 80° C. for 1 h in a sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 2:8 to 4:6) affording the title product (0.51 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.CS(C)=O>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
Into a 8-dram vial, 5-Bromo-2-nitro-pyridine (2.00 g, 9.85 mmol), Morpholine (1.12 g, 12.8 mmol), Triethylamine (1.37 mL, 9.85 mmol) and Dimethyl sulfoxide (10 mL, 100 mmol) were added. The reaction mixture was heated at 80° C. overnight. The reaction was cooled to RT and poured over ice. The solid was filtered and washed with water. The solid was washed with ethanol. The resulting solid was dried under vacuum to give 4-(6-Nitro-pyridin-3-yl)-morpholine as a white solid (1.60 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(=O)(O)[O-].[Na+].Br[CH2:18][C:19](Br)=[O:20]>C(Cl)(Cl)Cl>[O:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[O:11][CH2:18]1
Reactant: O=C(Br)CBr
Reactant: Nc1cc(C(=O)O)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 0 °C
Yield: 95 %

Procedure:
3-amino-4-hydroxybenzoic acid (4.0 g, 26.0 mmol) was dissolved in 168 mL of chloroform. 92 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (3.42 mL, 39 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 48 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) chromatogram indicated that all of the starting material was gone and a new peak (Rt=3.7 min) had formed. The reaction mixture was quenched using concentrated hydrochloric acid until the solution reached a pH of 2. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic layers were treated with 75 mL of 10% hydrochloric acid solution and separated once again. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (4.8 g, 24.7 mmol, 95%) as an off-white amorphous solid. MS (ES) m/e 194 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[C:21]5=[N:22][CH:23]=[CH:24][CH:25]=[C:20]5[NH:19][C:18]4=[O:26])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[N:9]=[CH:10]3)[C:18]1=[O:26])[CH3:29]
Reactant: CCI
Reactant: Cc1ccc(-n2ncc3cc(-n4c(=O)[nH]c5cccnc54)ccc32)nc1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc3c(cnn3-c3ccc(C)cn3)c2)c2ncccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A mixture of 3-[1-(5-methylpyridin-2-yl)-1H-indazol-5-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (70 mg) and iodoethane (35.1 mg) in DMF (2 mL) was stirred at 50° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane. The product was crystallized from AcOEt/Hexane to give the title compound as white crystals (25.0 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])O)[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[Cl:25])[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N#CCCN(Cc1ccccc1)CC(O)c1ccccc1Br
Solvent: ClCCl
Product: N#CCCN(Cc1ccccc1)CC(Cl)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 94 g of product obtained in Step 2 are dissolved in 400 ml of methylene chloride. At ambient temperature, within a period of 1 hour, 90.5 ml of thionyl chloride are poured in dropwise. After stirring for 12 hours at ambient temperature, the reaction mixture is evaporated to dryness and then taken up in ether and filtered. The solid is taken up in 500 ml of 10% aqueous sodium carbonate solution and 1 litre of methylene chloride. After separating off, drying and evaporating under reduced pressure, 90.2 g of expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][C:4]=1[C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)Cc1ccccc1

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 56 using 4-(4-methoxyphenoxy)-5-methyl-7-nitroindane instead of ethyl N-[7-(4-methoxyphenoxy)-6-methylindan-4-yl]malonamate and using phenylacetic acid instead of 4-fluorophenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH2:33][N:32]3[CH:40]=[CH:41][CH:42]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH:42]1[CH:41]=[CH:40][N:32]2[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:12](=[O:13])[CH2:11][C:3]4[S:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=5[C:2]=4[CH3:1])=[CH:44][CH:43]=3)=[O:28])[CH2:30][C:31]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1c(CC(=O)Cl)sc2ccccc12
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CC(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)sc2ccccc12
Reaction time: 0.05 h
Yield: 39.5 %

Procedure:
To a stirred solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. An additional 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride, 0.346 g of triethylamine and 30 mg of dimethylaminopyridine is added and stirring continued for an additional 18 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.320 g of the desired product as a yellow foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH3:21]
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CNC
Product: CN(C)c1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 76 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and dimethylamine in 76% yield, using the procedure described for example 37 and was characterized by its mass spectrum as follows: MS (m/z): 268 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:20]3[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccc(F)cc3)c2CN)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CNC(=O)N3Cc2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 4-[2-aminomethyl-3-(4-fluoro-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (255 mg, 0.62 mmol) in CH2Cl2 (6 ml) was cooled to 0° C. and NEt3 (0.19) ml, 1.36 mmol) and triphosgen (64 mg, 0.22 mmol) were added. After stirring at 0° C. for half an hour, the reaction mixture was allowed to warm up to room temperature and was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[1-(4-fluoro-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. (179 mg, 66%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)#[CH:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:27]=[CH:28][CH:29]=1)#[CH:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: C#Cc1cccc(C=O)c1
Product: C#Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-ethynylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-ethynylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](F)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Fc1cc(Cl)cc2cccnc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)cc3cccnc23)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
6-Chloro-8-fluoroquinoline (for example, as prepared for Intermediate 5) (2.18 g, 12 mmol) was dissolved in NMP (20 ml) and treated with 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Acros and/or Aldrich) (4.85 g, 24 mmol) and sodium tert-butoxide (2.38 g, 25 mmol). Further NMP was added (5 ml) and the resulting mixture was stirred at 140° C. for 1 h, and then allowed to cool overnight. The reaction mixture was treated with water and extracted with toluene. The organic extract was washed with water (×3), dried (MgSO4), and concentrated in vacuo. The residue was purified by silica chromatography (2×70 g), eluting with 0-100% EtOAc-cyclohexane over 30 min. The relevant fractions were concentrated in vacuo to give the title compound as a yellow gum (2.73 g, 63%): LCMS RT=3.37 min, ES+ve m/z 363/365 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:15][CH2:13][C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)=[O:14]
Reactant: [Br-]
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 16.6 g (0.074 mol) of 1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanone in 150 ml of dry tetrahydrofuran, were added portionwise at room temperature 27.8 g (0.074 mol) of phenyltrimethylammonium tribromide. The solution was stirred for 3 hours at room temperature. The formed solid was removed by filtration and the mother liquors were concentrated under vacuum. The resulting orange oil (32.7 g) was purified by flash chromatography on silica gel (eluent:heptane/dichloromethane 3:1) to give 2-bromo-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanone: 10.4 g (46%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].C1COCC1.S(Cl)([Cl:21])(=O)=O>O>[Cl:21][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1CC(=O)O
Temperature: -15 °C
Yield: 95 %

Procedure:
A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15° C. and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](O)=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.C([N:20](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([NH2:20])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccccc2)c1CCC(N)=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.95 g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 91%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 149–151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:42]1([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:44][CH2:43]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:49]2[CH2:50][CH2:51][N:46]([CH2:45][CH:42]3[CH2:44][CH2:43]3)[CH2:47][CH2:48]2)=[O:10])=[N:4][CH:3]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ncc(Br)cn1)N1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 28.9 %

Procedure:
To 5-bromopyrimidine-2-carboxylic acid (100 mg, 0.49 mmol) and TBTU (158 mg, 0.49 mmol) in anhydrous DMF 94.4. mL) was added DIPEA (0.36M in CH2Cl2, 1.4 mL, 0.49 mmol) and the reaction mixture stirred at RT for 40 min. N-cyclopropylmethylpiperazine (83 mg, 0.59 mmol) in anhydrous DMF (1 mL) was added and the reaction stirred at RT for 18 h. The reaction mixture was passed through a Si—NH2 cartridge (5 g), eluting with DMF and MeOH. The eluents were combined, concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain (5-bromo-pyrimidin-2-yl)-(4-cyclopropylmethyl-piperazin-1-yl)-methanone as a pale yellow solid (46 mg, 29%).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N[CH2:7][C:8](N)([CH3:10])[CH3:9]>N1C=CC=CC=1>[CH3:7][C:8]1([CH3:10])[CH2:9][NH:5][S:1](=[O:3])(=[O:2])[NH:4]1
Reactant: CC(C)(N)CN
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CC1(C)CNS(=O)(=O)N1
Yield: 84.9 %

Procedure:
To a refluxing solution of sulfamide (27.25 g, 283 mmol) in anhydrous pyridine (300 ml) was added dropwise 1,2-diamino-2-methylpropane (25 g, 283 mmol) over 2 hours. The resulting mixture was refluxed for further 16 hours under nitrogen before the solvent was removed under vacuum. The residue was triturated with hexane and the solid was collected by filtration and purified by flash chromatography (silica gel, dichloromethane-methanol 96:4) to give 36.1 g (85%) of the title compound as a white solid; mp 80°-83° C.; δH (360 MHz, DMSO-d6) 7.08 (1H, br t, --NH--), 6.77 (1H, s, --NH--), 3.04 (2H, d, J=6.9 Hz, --CH2 --), 1.24 (6H, s, --CMe2); m/z (EI) 151 (M+ +1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:2]1
Reactant: CCCCCCCCCBr
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of indole-3-carboxylic acid, 1-bromononane and potassium carbonate in N,N-dimethylformamide was stirred at room temperature for 15 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The solid was collected and washed with hexane to give nonyl indole-3-carboxylate.