Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:19]1([CH2:22][C:23]2[C:28]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)=O)[N:30]=3)=[CH:27][N:26]=[C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:24]=2)[CH2:21][CH2:20]1>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:31]2[N:30]=[C:29]([C:28]3[C:23]([CH2:22][CH:19]4[CH2:21][CH2:20]4)=[N:24][C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])=[N:26][CH:27]=3)[CH:34]=[CH:33][N:32]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Reactant: Nc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccnc(Cl)c3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 hour. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (29 mg, 49%).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=O)[CH:6]=1)([CH3:4])[CH3:3].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>C(O)C>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: N#CCC#N
Reactant: CC(C)(O)c1cc(C=O)no1
Solvent: CCO
Product: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
4.63 g of 5-(1-hydroxy-1-methylethyl)isoxazole-3-carbaldehyde was dissolved in 50 ml of ethanol, and 1.98 g of malononitrile was then added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 5.35 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O.C1C(=O)N([O:19][C:20]([O:22][N:23]2[C:28](=[O:29])[CH2:27][CH2:26][C:24]2=[O:25])=[O:21])C(=O)C1.C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:19][C:20](=[O:21])[O:22][N:23]1[C:24](=[O:25])[CH2:26][CH2:27][C:28]1=[O:29]
Reactant: COCCOCCOCCO
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCOCCOCCOC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Triethylene glycol monomethyl ether (1.0 g, 6.1 mmol) and N,N′-disuccinimidyl carbonate (1.87 g, 7.3 mmol) were dissolved in acetonitrile (10 mL). Then triethylamine (1.3 mL, 9.15 mmol) was added and the reaction stirred overnight at room temperature. Crude reaction was evaporated to dryness, dissolved in sat. NaHCO3 (50 mL), washed ethyl acetate (2×50 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 1 a clear oil (0.367 g, 20% yield).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(Cl)c3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.17 min; [M+H]+=425.94.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:18])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:2][C:3]1[C:4]([F:18])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2cc(F)c(F)cc2Nc2sccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 63 h
Yield: 48.7 %

Procedure:
Combine 6,7-difluoro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (876.9 mg, 3.05 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (1.32 g, 9.16 mmol), DMSO (3.0 ml), and toluene (12.0 ml). Stir and heat the mixture at 105° C. After 63 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 561.6 mg (49%) of the title compound: mass spectrum (ion spray): m/z=379.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][C:20]=1[F:21].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][C:20]([F:21])=[C:15]([F:14])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(F)c(F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
1.3 ml of 4-tert-butylbenzaldehyde (7.75 mmol) and 1 g of 2-(3,4-difluoro-phenyl)-ethyl-amine hydrochloride (5.16 mmol) and 714 mg of potassium carbonate (5.16 mmol) were suspended in 15 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 293 mg (7.75 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 4 h. After cooling down to rt, the reaction mixture was treated with 1 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 584 mg yellow oil (37%). MS (ISP) 304.2 (M+H)+.
Reaction SMILES: BrC1C=CC(O)=CC=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1.CC(C)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH:11]=1)[NH2:17]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: Oc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
A portion of 4-bromophenol is converted to 4-bromo-2-nitrophenol by the method described in Rec. Trav. Chim. 29, 187(1910). A 28 g. portion of 4-bromo-2-nitrophenol is dissolved in 280 ml. of acetone. A 280 ml. portion of water and 112 g. of Na2S2O4 are added with stirring. The mixture is refluxed for 2 hours, cooled to room temperature and extracted six times with ether. The ether extracts are washed twice with brine, dried over magnesium sulfate and recrystallized from a mixture of charcoal and 400 ml. of water giving an oil. This oil is redissolved in 600 ml. of water, cooled to 0° C. and filtered giving 5-bromo-2-hydroxyaniline as tan crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14].B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH3:34])([CH3:33])[CH2:11][C:12]([OH:32])([C:28]([F:29])([F:30])[F:31])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[O:25])[O:23][N:22]=[C:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:14]
Reactant: COc1cccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(=O)onc(C)c3c2)C(F)(F)F)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cccc(O)c3Br)C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
78 mg of (+)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is mixed in 1.4 ml of dichloromethane at 0° C. with 0.71 ml of a 1 molar solution of boron tribromide in dichloromethane. After 2 hours of stirring at 0° C., the mixture is added to water, extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. After the residue is triturated with hexane, the title compound is obtained in crystalline form, flash point 226–231° C., [α]D=+91.1° (c=0.5 in chloroform)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[OH:26]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[OH:26])=[O:13]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C(O)c1c(Br)sc2c1CCCC2
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1O)c1c(Br)sc2c1CCCC2

Procedure:
In the same manner as in Starting Material Synthesis Example 60 and using 2-bromo4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5-fluorophenol, 2-bromo-4,5,6,7-tetrahydro-N-(4-fluoro-2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide is obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 86.2 %

Procedure:
The same procedures as in Example 2 were carried out from methyl D-tryptophanate hydrochloride (2.5 g), triethylamine (1.6 mL), 2-fluorocinnamic acid (2.0 g), WSC.HCl (2.3 g), and methylene chloride (80 mL), to give the captioned compound (3.1 g, 86%) as an oily product.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1>O1CCOCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:3]4[N:11]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[S:9][C:4]=4[N:5]=[C:6]([CH3:8])[N:7]=3)[CH2:37][CH2:36]2)=[O:34])=[CH:41][CH:42]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 70 °C
Yield: 73 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-5-methylthiazolo[5,4-d]pyrimidine (30 mg, 0.11 mmol) and triethylamine (22 μl, 0.16 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (38 mg, 0.16 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) to yield the title compound as a white solid (40 mg, 75%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[C:7]1=[O:8].[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].[ClH:35]>CN(C)C=O>[ClH:35].[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:15](=[O:16])[CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]3[C:7]2=[O:8])[CH2:25][CH2:24]1
Reactant: O=C1C2CCCCC2C(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C2CCCCC2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 9 h

Procedure:
A mixture of N-(4-bromobutyl)cyclohexane-1,2-dicarboximide (10.00 g), 1-(2-pyrimidyl)piperazine (4.75 g), anhydrous potassium carbonate powder (8.00 g) and anhydrous dimethylformamide (100 ml) was stirred at 100°-110° C. for 9 hours. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by chromatography to give an oily substance, which was then treated with hydrogen chloride to give N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]cyclohexane-1,2-dicarboximide hydrochloride. M.P., 168°-169° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([NH:19][CH:20]1[C:26](=[O:27])[N:25]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:21]1=[O:40])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:19][C@H:20]([C:26]([C:20]2([NH2:19])[C:26](=[O:27])[N:25]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:21]2=[O:40])=[O:27])[CH3:21])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white solid (melting point=211–212° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:8](=[O:9])[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:8](=[O:9])[N:7]1[C:32](=[O:33])[NH:31][CH:28]([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)n1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)n1c(=O)n(-c2cc(Cl)cc(Cl)c2)c(=O)n1C(=O)NC(C)C
Yield: 75 %

Procedure:
To a solution of 3.2 g of 1-ethoxycarbonyl-4-(3',5'-dichlorophenyl) urazole in 10 ml of N,N-dimethylformamide were added, in sequence, a drop of triethylamine and 0.85 g of isopropyl isocyanate dropwise at room temperature with agitation. After maintaining the same conditions for one hour, the reaction mixture was mixed with water to precipitate crystals which were filtered and recrystallized from ethanol to obtain 1-ethoxycarbonyl-2-(isopropyl carbamoyl)-4-(3',5'-dichlorophenyl) urazole in an amount of 3.0 g, a yield of 75%.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O>[CH3:33][S:34]([O:27][CH2:26][CH2:25][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:29])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:22][CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])(=[O:36])=[O:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0° C. To this mixture, TEA (50 μL, 0.0004 mol) was added. The reaction was stirred for 15 minutes. Methanesulfonyl chloride (23 μL, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-pentane-1,5-diyl dimethanesulfonate (57 mg, 80%) as an oil. MS (ES): 574 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([OH:15])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:25][CH2:26][CH3:27])([CH2:22][CH2:23][CH3:24])[CH2:3]1.Br[CH2:30][C:31]([O:33]CC)=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CC#N.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:30][C:31]([OH:33])=[O:32])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:5][C:4]([CH2:25][CH2:26][CH3:27])([CH2:22][CH2:23][CH3:24])[CH2:3]1
Reactant: CCCC1(CCC)CN(c2ccccc2)c2cc(SC)c(O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: CCCC1(CCC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 80 °C

Procedure:
To a suspension of 1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 117; 0.665 g, 1.58 mmol) in MeCN (10 ml) was added ethyl bromoacetate (0.262 ml, 2.35 mmol), tetrabutylammonium bromide (0.051 g, 0.158 mmol) and sodium carbonate (0.870 g, 8.21 mmol). The mixture was stirred over night at 80° C. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 0.5 M HCl. The organic layer was washed with brine, dried (MgSO4) and concentrated. The residue was filtered through a short silica column (DCM:EtOAc-9:1), concentrated and dissolved in EtOH (10 ml). A solution of NaOH (0.25 g, 6.25 mmol) in water (1 ml) was added and the solution was stirred over night at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 0.5 M HCl. The aqueous layer was extracted twice more with EtOAc and the combined organic extracts were washed with brine and concentrated. The crude product was purified by preparative HPLC using a MeCN/ammonium acetate buffer to give the title compound in 0.441 g (58%) as a white solid. NMR (DMSO-d6) 0.55–0.75 (m; 6H), 1.05–1.50 (m, 8H), 2.15 (s, 3H), 3.20 (s, 2H), 3.65 (brs, 2H), 4.50 (s, 2H), 6.65 (s, 1H), 6.80–7.00 (m, 3H), 7.15 (s, 1H), 7.15–7.25 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CN3CCOCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and morpholine to give a yellow solid. MS m/z: 405.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH3:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:28]=1[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[CH3:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:28]=1[CH2:29][C:30]1([NH:33][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=2)[OH:25])[CH2:32][CH2:31]1
Reactant: Cc1cccc(C)c1CC1(N)CC1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(C)c1CC1(NCC(O)c2ccc(O)c(CO)c2)CC1

Procedure:
Prepared according to general method 5 from 344 mg (1 mmol) methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 175 mg (1 mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine. Yield: 64 mg (14%, trifluoroacetate); mass spectroscopy: [M+H]+=342.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>N1C=CC=CC=1>[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([O:9][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])[CH:6]([CH3:8])[CH3:7])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)OCC(C)(C)C(OS(=O)(=O)c1ccccc1C(=O)OC)C(C)C
Temperature: 0 °C

Procedure:
Into a one-liter, four-necked, round bottom flask equipped with stirrer, condenser, thermometer and addition funnel, 36.5 parts of 2,2,4-trimethyl-1,3-pentanediol and 632.0 parts of pyridine were mixed under a nitrogen blanket and cooled to 0° C. using an ice water bath. Subsequently, 117.3 parts of o-carbomethoxybenzenesulfonyl chloride were added in small portions over a two hour period while maintaining the temperature below 10° C. The aforesaid mixture was maintained at a temperature between 0° C. and 10° C. for a two hour period and then refrigerated at 15° C. for at least twenty-four hours prior to work-up. For work-up the reaction mixture was poured into 1000 parts of ice water and subsequently extracted with 500 parts of methylene chloride. The organic layer was washed successively with cold, dilute 6N sulfuric acid (twice with 500 part-portions), cold, dilute sodium bicarbonate (once with 500 parts), and water (until the water layer was neutral to pH paper). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the 2,2,4-trimethyl-1,3-pentanediyl bis-(ortho-carbomethoxybenzenesulfonate).