Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19](O)=[O:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][S:29](=[O:32])(=[O:31])[NH2:30].CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][S:29](=[O:31])(=[O:32])[NH:30][C:19](=[O:20])[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:22])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCS(N)(=O)=O
Reactant: Cc1cc2c(OCC(=O)O)cccc2n1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCS(=O)(=O)NC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1-benzyl-2-methyl-1H-indol-4-yloxy)-acetic acid (5) (0.189 g, 0.64 mmole) in dichloromethane (15 mL), 4-sulfamoyl-butyric acid methyl ester (0.232 g, 1.28 mmole), EDCI (0.122 g, 0.64 mmole) and DMAP (0.078 g, 0.64 mmole) were added. The mixture was stirred at room temperature for 18 h. The dichloromethane was evaporated to half of the original volume and the mixture was washed with water (2×10 mL). The organic layer was separated and evaporated. The residue was purified by column chromatography (10:1 CHCl3:MeOH) to afford intermediate (6) as a solid. Yield: 0.15 g, 51%
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.O[Li].O>CO.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: COC(=O)CCNc1nc(Cl)cc2nccnc12
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of methyl 3-(7-chloropyrido[4,3-b]pyrazin-5-ylamino)propanoate (545 mg, 2.04 mmol) and LiOH.H2O (172 mg, 4.09 mmol) in MeOH/H2O (v. 20:1, 40 mL/2 mL) was stirred at room temperature for 20 hours. The volatiles were removed under reduced pressure, and the residue was acidified with HCl solution (1 N) till pH=2˜3. The precipitates were collected by filtration and dried to afford the title compound. MS (m/z): 253 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(C)C.[OH-].[K+]>CO.C1(C)C=CC=CC=1>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: C#Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 2 h

Procedure:
To a solution of 6-trimethylsilylethynyl-8-(3-nitrophenyl)-1,7-naphthyridine (77 mg, 0.22 mmol) in methanol (0.5 ml) and toluene (0.5 ml) is added 1N potassium hydroxide (0.22 ml). The mixture was stirred for 2 h. The suspension is filtered and the product washed with water and ether affording the title compound. Mass M+H 276; mp 215° C. decomposition.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Br[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32]([NH2:34])=[O:33]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=4)[C:32]([NH2:34])=[O:33])=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Reactant: NC(=O)c1ccnc(Br)c1
Product: NC(=O)c1ccnc(-c2n[nH]c3cnc(-c4cccnc4)cc23)c1
Yield: 21 %

Procedure:
Following the Stille coupling procedure of Example 299, 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and 2-bromoisonicotinamide were reacted. The product was deprotected by the procedure of Example 225 and purified via silica gel chromatography using a gradient of methanol in dichloromethane to afford 10 mg (21%) of 302 over two steps. ESI MS m/z 317.1 (M+1). 1H NMR (400 MHz, DMSO): 14.16 (s, 1H), 9.28 (d, J=12.0 Hz, 2H), 8.96 (s, 1H), 8.94 (d, J=5.1 Hz, 1H), 8.62 (d, J=5.3 Hz, 2H), 8.45 (d, J=8.0 Hz, 1H), 8.40 (s, 1H), 7.80 (d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.55 (dd, J=8.0, 4.7 Hz, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:5]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Product: O=S(=O)(NC1CNc2ccc(-c3ccccc3)cc2C1)c1ccccc1

Procedure:
Compound 170A was prepared from 87A and phenylboronic acid by procedures analogous to those described in Example 91A.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][C:14]([OH:18])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(CCO)on1
Reactant: O=S(=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 8.8 g of 2-[3-(4-chlorobenzoyl)isoxazol-5-yl)ethanol, 850 ml of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 130 ml of 9M H2SO4 was added 10.3 g of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 2 hours. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was extracted with CH2Cl2, and the organics were washed with water and brine, and dried over MgSO4. Concentration gave 5.1 g of a solid. Recrystallization from toluene gave 3.0 g (32%) of needles, m.p. 126°-128°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15]O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:18].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:18][CH2:15][C:13]1[N:12]=[N:11][N:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: BrP(Br)Br
Reactant: OCc1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(Cn2cc(CBr)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methanol (Intermediate 16) (0.17 g, 0.66 mmol) in DCM was added PBr3 (125 μL, 2 eq) and the reaction was stirred at room temperature for 3 hours. Water was added, followed by solid NaHCO3. The organic phase was dried over sodium sulphate and evaporated. The title compound was obtained as a colorless oil (0.21 g, 99%) and used in the next step without purification. LC/MS: m/z 320 (M−H)+. Rt: 2.13 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12](=[O:16])[N:13]([CH3:15])[CH2:14][C:8]=2[CH:7]=1.CS[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:12](=[O:16])[N:13]([CH3:15])[CH2:14][C:8]=2[CH:7]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCN)cc2CN(C)C1=O
Reactant: CSC1=NCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)CC1Cc2ccc(OCCCNC3=NCCN3)cc2CN(C)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A mixture of methyl (±)-8-[3-amino-1-propyloxy]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.3 g, 1 mmol), 2-methylthioimidazoline (0.46 g, 2 mmol), diisopropylethylamine (0.42 mL, 2 mmol) and dimethylacetamide (3 mL) was heated to 100° C. under argon. After 2 hr, the reaction was concentrated under vacuum and the residue was partitioned between CHCl3 and H2O. The organic phase was dried (MgSO4) and concentrated, and the residue was purified by preparative HPLC to give the title compound (0.24 g, 51%) as a yellow oil: MS (ES) m/e 389.4 (M+H)+.
Reaction SMILES: Cl.[C:2]1([P:8]2(=[O:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[O:14]=[P:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Reactant: O=P1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(CCN2CCP(=O)(c3ccccc3)CC2)cc1

Procedure:
4-Phenyl-1,4-azaphosphinane 4-oxide hydrochloride (200 mg, 0.863 mmol), tert-butyl 4-(2-bromoethyl)benzoate (246 mg, 0.863 mmol), and K2CO3 (358 mg, 2.59 mmol) were combined in MeCN (10 mL) and stirred at reflux overnight. The reaction was cooled, diluted with EtOAc, washed with water and brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded the title compound as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.88 (d, J=8.4 Hz, 2H), 7.76-7.71 (m, 2H), 7.54-7.45 (m, 3H), 7.21 (d, J=8.2 Hz, 2H), 3.09-2.99 (m, 4H), 2.85-2.80 (m, 2H), 2.77-2.73 (m, 2H), 2.19-2.11 (m, 2H), 2.08-1.98 (m, 2H), 1.55 (s, 9H). MS: cal'd 400 (MH+), exp 400 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][C:10](=S)[S:11]C)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:17][NH2:18]>C(O)C>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][C:10](=[S:11])[NH:17][NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CSC(=S)NCc1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=S)NCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 187 g (772 mmole) of methyl N-(4-nitrobenzyl)dithiocarbamate and 450 ml of hydrazine hydrate in 1400 ml of absolute ethanol was stirred mechanically and heated to reflux. Precipitation began by the time the internal temperature reached about 40° C. After 2 hours at reflux, the mixture was cooled and allowed to stand at room temperature. The solid was collected on a filter, washed with ethanol, and dried to give 105 g (60%) of light yellow crystals, mp 196°-198° C. satisfactory purity by TLC in 95:5:0.5 CH2Cl2 --MeOH-concd NH4OH; mass spectrum (FAB) m/e 227 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[C:12]([NH:16][C:17]([C:19]1[O:20][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:21]3[O:20][C:19]([C:17]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(C)NC(=O)c1ccc(CN2CCNCC2)o1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)o1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of 4-amino-3-fluorobenzoic acid (0.883 g, 5.69 mmol), N-tert-butyl-5-(piperazin-1-ylmethyl)furan-2-carboxamide (1.51 g, 5.69 mmol) and triethyl-amine (0.576 g, 5.69 mmol, 0.791 mL) in dichloromethane was added 1-propanephosphonic acid cyclic anhydride (3.62 g, 5.69 mmol, 3.39 mL, 50% solution in ethyl acetate). The reaction was stirred for 2 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with sodium bicarbonate, water and brine. The organic phase was concentrated under reduced pressure to give the title compound (0.93 g). MS (ESI) m/z 403.6 [M+H]+
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH2:33]([SH:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(O)C>[CH2:1]([O:17][CH2:18][CH:19]([CH2:25][S:49][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOCC(CSCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 8 h

Procedure:
To a solution of 20 g of 2-[(hexadecyloxy)methyl]-2-propenoic acid, ethyl ester and 10 ml of triethylamine in 60 ml of ethanol is added 53 ml of hexadecyl mercaptan. This mixture is stirred overnight, then the solvents removed and the residue purified by HPLC [hexane:ethyl acetate (9:1)], to give 32.9 g of the desired compound as a white waxy solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH:13][CH:14]([C:16]1[N:17]=[CH:18][N:19]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]=1[CH3:21])[CH3:15].C1CCN2C(=NCCC2)CC1.[O:52]1CCC[CH2:53]1>C(OCC)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:53](=[O:52])[N:13]([CH:14]([C:16]3[N:17]=[CH:18][N:19]([C:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:20]=3[CH3:21])[CH3:15])[CH2:12][CH2:11][C:3]=12
Reactant: C1CCOC1
Reactant: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)[nH]c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1c2n(c3ccccc13)C(=O)N(C(C)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2

Procedure:
A mixture of 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]indole (262 mg), N,N'-carbonxyldiimidazole (210 mg), 1.8-diazabicyclo[5.4.0]-7-undecene (84 mg) and molecular sieves (100 mg) in dry tetrahydrofuran (3 ml) was stirred at reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% methanol in chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]-pyrimido[1,6-a]indol-1(2H)-one (208 mg) as glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])([CH3:20])[CH3:19])[C:12]2=[O:28])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][CH2:38][N:39]([CH3:50])[C:40](=[O:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([CH3:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:37][CH2:38][N:39]([CH3:50])[C:40]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:49])[CH3:19])[C:12]2=[O:28])[CH:5]=1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3O)c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCN(C)C(=O)OCc3ccccc3)c2=O)c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
To 3-[3-[[1-(2-Hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 220b, 2.495 g) in acetonitrile (150 mL) was added potassium carbonate (1.753 g) followed by benzyl 2-chloroethyl(methyl)carbamate (J. Med. Chem., 1992, 35 (17), 3246, 1.660 g) and the reaction heated at 85° C. for 72 h under nitrogen. Further benzyl 2-chloroethyl(methyl)carbamate (0.58 g) and potassium carbonate (0.35 g) were added and the reaction stirred for 2 days. The reaction mixture was cooled, evaporated to dryness and the residue partitioned between water and dichloromethane and the organic layer separated. The aqueous was further extracted with dichloromethane (2×) and the combined organics dried (Na2SO4) and evaporated. Purification (SiO2 chromatography eluting with 40-100% ethyl acetate) gave the subtitle product (1.97 g).
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[S:12][CH:11]=[C:10]([CH:13]([N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:14][OH:15])[CH:9]=2)[O:4]C1.O>CC(O)=O.O>[CH:5]([C:8]1[S:12][CH:11]=[C:10]([CH:13]([N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:14][OH:15])[CH:9]=1)=[O:4]
Reactant: CC(C)CCN(C(CO)c1csc(C2OCC(C)(C)CO2)c1)S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCN(C(CO)c1csc(C=O)c1)S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
N-{1-[5-(5,5-dimethyl-1,3-dioxan-2-yl)thiophen-3-yl]-2-hydroxyethyl}-N-(3-methylbutyl)benzenesulfonamide was dissolved in 10 mL AcOH/water (4:1) and stirred for 5 hours. 5 mL of water was and the aqueous layer was extracted 2× with EtOAc. The EtOAc layers were combined, washed 3 times with water, once with brine and dried (MgSO4). The residue was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1cc(OC)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(OC)nc(NC2CCNCC2)n1

Procedure:
A solution of 4-(4,6-dimethoxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 5.82 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 239.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:16]3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1.[CH2:45]([O:48]CC=C)[CH:46]=[CH2:47].[Na].CN(C=O)C>C(OCC)(=O)C>[CH2:45]([O:48][C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:16]3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1)[CH:46]=[CH2:47]
Reactant: C=CCOCC=C
Reactant: CS(=O)(=O)c1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1nc(S(C)(=O)=O)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A solution of 10 g of 4chloro-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 1.35 g of sodium allyloxide, and 50 ml of DMF is stirred at ambient temperature for 24 hours, evaporated in vacuo and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water and the dried ethyl acetate extracts are evaporated in vacuo to provide crude product. Chromatography of this material over silica gel with ethyl acetate provides pure 4-allyloxy-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[S:10](Cl)(Cl)=O.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][S:10][N:9]=[C:4]2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=S(Cl)Cl
Agent: O=S(=O)(O)O
Product: Clc1ccc2nsnc2c1

Procedure:
A mixture was prepared by mixing 4.0 g (28 mmol) of 4-chloro-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resultant precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.6 g of 5-chloro-2,1,3-benzothiadiazole as a crude product (melting point, 50 to 54° C.; yield, 96%). This crude product was vacuum-distilled to yield a pure product of 5-chloro-2,1,3-benzothiadiazole (melting point, 54° C.; yield, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>S(Cl)(Cl)=O.CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]([O:36][C:34](=[O:35])[C:33]1[CH:39]=[CH:40][C:30]([NH:29][C:14](=[O:15])[CH:13]([N:12]2[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:31][CH:32]=1)[CH3:38]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
The solution of 3.0 g (7.4 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 5.4 ml thionylchloride was stirred under reflux. After 1 h the volatile components were removed at a rotary evaporator, the residue taken up in toluene and evaporated (three times). The remaining oil was dissolved in 30 ml dichloromethane, cooled to 0° C. and added dropwise on a solution of ethyl 4-aminobenzoate (1.35 g, 8.1 mmol) and 2.72 g (22.2 mmol) 4-dimethylaminopyridine dissolved in 30 ml dichloromethane. The cooling bath was removed and stirring was continued for another 4 h. The reaction was poured on 25% aqueous hydrochloric acid solution, the phases separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using heptane:ethyl acetate (1:0 to 1:1 v/v) as eluant to afford the title compound as a colorless solid (2.6 g, 62%).