Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]1=[O:18].C(N(C(C)C)CC)(C)C.[N:29]([CH2:32][C:33]([O:35]CC)=[O:34])=[C:30]=[O:31]>ClCCl>[OH:11][C:10]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6](=[O:18])[N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:12])[C:9]=1[C:30]([NH:29][CH2:32][C:33]([OH:35])=[O:34])=[O:31]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(CCC(C)C)c1=O
Reaction time: 5 h

Procedure:
-{[6-Hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture of 1,3-bis(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.2 g, 4.47 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (501 uL, 4.47 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (430 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br. s, 1 H), 10.11 (s, 1 H), 4.09-4.16 (m, 2 H), 3.77-3.86 (m, 4 H), 1.51-1.62 (dt, J=13.29, 6.59, 6.59, 6.59, 6.59 Hz, 2 H), 1.42 (q, J=7.07 Hz, 4 H), 0.91 (d, J=6.57 Hz, 12 H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:15][C:16](Cl)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[F:20][C:21]([F:46])([F:45])[C:22]1[CH:23]=[C:24]([S:32]([NH:35][C:36]2[S:37][C:38]3[CH2:39][NH2+:40][CH2:41][CH2:42][C:43]=3[N:44]=2)(=[O:34])=[O:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH:10]1([CH2:15][C:16]([N:40]2[CH2:41][CH2:42][C:43]3[N:44]=[C:36]([NH:35][S:32]([C:24]4[CH:23]=[C:22]([C:21]([F:20])([F:45])[F:46])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=4)(=[O:34])=[O:33])[S:37][C:38]=3[CH2:39]2)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: O=S(=O)(Nc1nc2c(s1)C[NH2+]CC2)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CCCC1)N1CCc2nc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)sc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIEA and cyclopentyl-acetyl chloride are added at 0° to a mixture of 75 mg of 2-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-5-ium hydrochloride salt in CH2Cl2. The mixture obtained is stirred at RT for 4 hours, 2 ml of 1 M aqueous NaHSO4 solution are added and two phases formed are separated. The organic layer obtained is concentrated and subjected to preparative HPLC (RP-18). N-[5-(2-Cyclo-pentyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl]-3,5-bis-trifluoromethyl-benzene-sulfonamide is obtained.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[S:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Solvent: Cc1ccccc1
Product: S=c1c2c(c3cccnc3n1-c1ccccc1)OCC2

Procedure:
A suspension of 3,5-dihydro-5-phenyl-furo-[3,2-c][1,8]naphthyridin-4(2H)-one (3 g.) and 2,4-bis- (4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent; 5 g.) in dry toluene (100 ml.) was stirred in an atmosphere of nitrogen and heated to reflux for 6 hrs. After cooling, the organic layer was washed with water, dried and evaporated. The product was purified by chromatography over silica gel in CH2Cl2 containing increasing amounts of ethyl acetate (0-5%). The fractions containing pure product were combined, evaporated, suspended in ethanol, filtered and dried to yield the desired product, m.p. 242°-244.5° C.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][O:31][C@@H:30](O)[CH:29]3[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[N:28]23)=[CH:23][CH:22]=1.O>ClCCl.C(OCC)(=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]2[CH2:32][O:31][CH:30]=[C:29]3[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[N:28]23)=[CH:25][CH:26]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]2[CH2:32][O:31][CH2:30][C@H:29]3[CH2:34][CH2:35][CH2:36][C:37](=[O:38])[N:28]23)=[CH:25][CH:26]=1
Reactant: O=C1CCCC2[C@H](O)OCC(c3ccc(F)cc3)N12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C1CCCC2=COC[C@@H](c3ccc(F)cc3)N12
Product: O=C1CCC[C@@H]2COC[C@@H](c3ccc(F)cc3)N12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Triethylsilane (5.5 mL) and trimethylsilyl trifluoromethanesulfonate (442 μL) were added to a solution of (R*)-4-(4-fluorophenyl)-1-hydroxyhexahydropyrido[2,1-c][1,4]oxazin-6-one (324 mg) in dichloromethane (10 mL), and the reaction solution was reacted at room temperature for 1.5 hours. Then, the reaction solution was heated to 60° C. and stirred for two hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 69.2 mg of (R*)-4-(4-fluorophenyl)-3,4,8,9-tetrahydro-7H-pyrido[2,1-c][1,4]oxazin-6-one and 52.8 mg of (4R*,9aR*)-4-(4-fluorophenyl)hexahydropyrido[2,1-c][1,4]oxazin-6-one. The physical properties of (R*)-4-(4-fluorophenyl)-3,4,8,9-tetrahydro-7H-pyrido[2,1-c][1,4]oxazin-6-one are as follows.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[C:10]([CH2:11]Cl)=[C:9]([CH3:13])[S:8][C:7]=1[CH3:14].C[N:16]([CH:18]=O)C>C(Cl)(Cl)Cl.[Na+].[Cl-]>[C:1]([CH2:5][C:6]1[C:10]([CH2:11][C:18]#[N:16])=[C:9]([CH3:13])[S:8][C:7]=1[CH3:14])#[N:2]
Reactant: CN(C)C=O
Reactant: Cc1sc(C)c(CCl)c1CCl
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1sc(C)c(CC#N)c1CC#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A suspension of potassium cyanide (13.2 g, 203 mmol) in DMF (66 mL) is cooled to 0° C. and carefully treated with a solution of 3,4-bis-chloromethyl-2,5-dimethyl-thiophene (10.0 g, 48.0 mmol) in DMF (34 mL). After warming to room temperature and stirring for 18 h, the solution is heated to 40° C. for 1 h, cooled to room temperature and diluted with chloroform and saturated aq NaCl. The chloroform layer is separated, and the aq layer extracted with chloroform. The combined organic layers are washed with saturated aq NaCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is triturated with heptane, filtered under vacuum and dried overnight in a vacuum oven to give (4-cyanomethyl-2,5-dimethyl-thiophen-3-yl)-acetonitrile (8.6 g, 94.6%) as an off-white solid: mp 123.5-125.5° C.; Rf 0.33 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 3.65 (s, 4 H), 2.38 (s, 6 H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylacetyl chloride (9.4 g) was added dropwise to 4-bromophenol (10 g) in pyridine, and the reaction mixture was stirred at room temperature for 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4-bromophenyl phenylacetate.
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[C:8](N)[C:9](F)=[C:10](F)[C:11]=2F)[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)C.C(NCC1CCNC1)C.C(N(CC)CC)C>C(#N)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][CH:4]=[C:5]1[C:18]([OH:20])=[O:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(F)c(F)c21
Agent: CCNCC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 3.02 g (10 mmole) of 1-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic acid, 1.93 g (15 mmole) of N-ethyl-3-pyrrolidinemethanamine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1-ethyl-5-amino-6,8-difluoro-7-[3-(ethylamino)methyl-1-pyrrolidinyl)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:3]=1.CN(C1C=CC=CN=1)C.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:37]2[CH2:36][CH2:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:39][CH2:38]2)=[O:7])=[C:4]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(C(=O)O)c(NC(=O)C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
1.12 g (0.00453 mol) of 4-methyl-2-trifluoroaceta-mido-benzoic acid were dissolved in 23 ml of dimethylformamide, treated with 0.277 g (0.00227 mol) of dimethylaminopyridine and cooled to 00. 0.867 g (0.00453 mol) of 1-benzyl-4-hydroxy-piperidine and 0.955 g (0.005 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the mixture was stirred at 0° for 2 hrs. Thereafter, the mixture was warmed to room temperature. The mixture was stirred at room temperature for 48 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate and washed with semi-sat. sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 1.27 g (77%) of 1-benzyl-piperidin-4-yl 4-methyl-2-trifluoroacetamido-benzoate were obtained as a yellow oil. MS: me/e=421 (C22H24F3N2 O3 +).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:16][C:15]([F:17])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
1.08 g (12.5 mmol) of piperazine are placed in the presence of 1 g (4.2 mmol) of 1-bromomethyl-2-trifluoromethyl-benzene and 0.64 mL (4.6 mmol) of triethylamine in 10 mL of toluene. The reaction medium is stirred for 30 min at room temperature and then heated to 110° C. for 6 h. After dry concentration, the obtained residue is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phases are dry concentrated, the obtained residue is purified by flash chromatography on silica (CH2Cl2-MeOH—NH4OH: 90-9-1). 0.7 g of intermediate 7a are thereby isolated as a clear oil (yield 68%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]([OH:16])=O)[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]([N:30]=[N+:31]=[N-:32])=[O:16])[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1cc(C=CC(=O)O)ccc1C
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(C=CC(=O)N=[N+]=[N-])ccc1C
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a slurry of 3-(3-acetamido-4-methylphenyl)propenoic acid (20.11 g, 91.7 mmol) in acetone (450 mL) at 0° C. is added triethylamine (12.8 mL, 91.8 mmol) followed by dropwise addition of ethyl chloroformate (11.8 mL, 123 mmol) over a 10 minutes period. The resulting yellow slurry is stirred using a mechanical stirrer for 1.5 hours, then a solution of sodium azide (8.94 g, 138 mmol) in water (25 mL) is added slowly so as to maintain the temperature below 5° C. The thick mixture is stirred at 0° C. for 1 hours, then the ice bath is removed and the reaction mixture allowed to warm to room temperature. The suspension is poured over water (800 mL) then filtered. The remaining solid is washed generously with water and dried under vacuum over P2O5 overnight to give the product as a pale yellow solid (21.40 g, 87.6 mmol).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1>>[CH:31]1([CH2:30][O:29][C:21]2[CH:20]=[C:19]([C:13]3[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:38]5[C:34](=[O:40])[CH2:35][CH2:36][C:37]5=[O:39])[CH2:6][CH2:7]4)[N:12]=3)[CH:24]=[CH:23][C:22]=2[O:25][CH:26]([F:27])[F:28])[CH2:32][CH2:33]1
Reactant: CC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=C1CCC(=O)N1
Product: CC1(C)C(=O)N(C2CCN(C(=O)CN3C(=O)CCC3=O)CC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A3) and succinimide as starting compounds.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[N:25]2[CH:26]=[CH:27][S:28][C:24]2=[N:23][CH:22]=[C:21]1[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:29]([C:21]2[C:20](=[O:19])[N:25]3[CH:26]=[CH:27][S:28][C:24]3=[N:23][CH:22]=2)=[O:30])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1cnc2sccn2c1=O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cnc3sccn3c2=O)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (500 mg), 5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylic acid (371 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (395 mg), 1-hydroxy-1H-benzotriazole monohydrate (315 mg), triethylamine (0.558 mL), and N,N-dimethylformamide (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (320 mg, 47%) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.O.ClC1C=CC([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:17])=CC=1.C1(C)C=CC(S(O)(=O)=[O:34])=CC=1>C(O)CO>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH:16]2[O:17][CH2:7][CH2:1][O:34]2)=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: Cc1ccccc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(C2OCCO2)cc1

Procedure:
Toluene (1900 ml) was stirred in a round-bottom flask (5 l) using a water separator. (4-chlorophenyl)(4-nitrophenyl)methanone (250 g) was added portionwise. p-Toluene-sulfonic acid (54.5 g) was added portionwise. Ethylene glycol (237.5 g) was poured out into the mixture. The mixture was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was dissolved into ethyl acetate (5 l) and washed twice with a K2CO3 10% solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried (vacuum, 40° C., 24 hours), yielding 265 g (91%) of 2-(4-chlorophenyl)-2-(4-nitrophenyl-1,3-dioxolane (interm. 7-a).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[S:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:41])=[O:40])[CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (0.0075 g, 0.061 mmol), benzenesulfonyl chloride (0.108 g, 0.610 mmol), and Hünig's base (0.159 mL, 0.915 mmol). The resulting mixture was stirred at room temperature. After 2 h, the mixture was concentrated and the crude product was purified by column chromatography (40 g of silica, 10 to 40% acetone in hexanes) to give N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)benzenesulfonamide (0.176 g) as a mixture of two isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>C(NCC)C.C(Cl)Cl.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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:18][C:6]=4[C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]=23)=[CH:22][CH:21]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccc(Cl)cc3)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.6 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 16 hours with 1.5 g (11 mmol) of p-chlorophenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 35 ml of diethylamine. The reaction mixture was diluted with 175 ml of methylene chloride and washed three times with water. The organic phase was dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel and subsequent recrystallization from methylene chloride and ethyl acetate there was obtained 3-[(p-chlorophenyl)ethynyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 221°-222°.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Si:33]([O:50][CH2:51][C@@H:52]1[CH2:57][O:56][CH2:55][CH2:54][NH:53]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Si:33]([O:50][CH2:51][C@H:52]1[N:53]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:17][C:16]=2[S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:54][CH2:55][O:56][CH2:57]1)([C:46]([CH3:47])([CH3:48])[CH3:49])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
(R)-4-(Phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 0.8 g, 1.60 mmol) was added to a solution of (S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholine, hydrochloride salt (INTERMEDIATE 103, 0.57 g, 1.60 mmol), DIPEA (0.84 ml, 4.81 mmol) and HATU (0.92 g, 2.41 mmol) in DCM (10 ml) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with H2O (2×), 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography (ISCO, eluting with 0→100% DCM/10% MeOH in DCM) to provide the title product (0.5 g, yield: 37%).
Reaction SMILES: N#N.[SH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[SiH4].[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCCCCC.C(N(CC)CC)C>[C:18]([S:3][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: CCCCCCCC(=O)Cl
Agent: N#N
Agent: [SiH4]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Yield: 86.8 %

Procedure:
Into a 12-liter, three-necked round bottom flask equipped with mechanical stirrer, addition funnel, thermocouple, heating mantle, N2 inlet, and temperature controller were charged 1,021 grams of 3-mercaptopropyltriethoxysilane (SILQUEST® A-1891 silane from OSi Specialties, Inc., a subsidiary of Crompton Corp. of Greenwich, Conn.), 433 grams of triethylamine, and 3,000 ml hexane. The solution was cooled in an ice bath, and 693 grams of octanoyl chloride were added over a two-hour period via the addition funnel. After addition of the acid chloride was complete, the mixture was filtered two times, first through a 0.1:m filter and then through a 0.01:m filter, using a pressure filter, to remove the salt. The solvent was removed under vacuum. The remaining yellow liquid was vacuum distilled to yield 1,349 grams of 3-(octanoylthio)-1-propyltriethoxysilane as a clear, very light yellow liquid. The yield was 87 percent.