Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.CN(C)C1C=CC=CC=1.Cl.[CH2:40]([O:42][N:43]=[C:44]([C:48]1[N:52]=[C:51]([NH2:53])[S:50][N:49]=1)[C:45](Cl)=[O:46])[CH3:41].Cl>C(Cl)Cl.O>[CH2:40]([O:42][N:43]=[C:44]([C:48]1[N:52]=[C:51]([NH2:53])[S:50][N:49]=1)[C:45]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12)=[O:46])[CH3:41]
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 88.4 %

Procedure:
To a suspension of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (27 g) in methylene chloride (300 ml) was added N,N-dimethylaniline (36.2 g) under cooling in an ice bath at 5° C. To the solution was added portionwise 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (16.2 g) below 11° C. and the mixture was stirred for 45 minutes at 5° C. The reaction mixture was diluted with a mixed solvent of methylene chloride (100 ml) and water (200 ml) and adjusted to pH 2 with 1N hydrochloric acid. The organic layer was separated out, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (32.4 g), mp 120° to 125° C. (dec.).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:26]C)=[C:13]([C:15]2[C:23]3[CH2:22][NH:21][C:20]([NH2:24])=[N:19][C:18]=3[N:17]([CH3:25])[N:16]=2)[CH:14]=1.[BrH:28]>O>[NH2:24][C:20]1[N:19]=[C:18]2[N:17]([CH3:25])[N:16]=[C:15]([C:13]3[CH:14]=[C:9]([Cl:8])[CH:10]=[C:11]([Br:28])[C:12]=3[OH:26])[C:23]2=[CH:22][N:21]=1
Reactant: Br
Reactant: COc1ccc(Cl)cc1-c1nn(C)c2c1CNC(N)=N2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(Cl)cc(Br)c2O)c2cnc(N)nc21

Procedure:
3-(5-Chloro-2-methoxy-phenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine trifluoroacetate is dissolved in 48% HBr in water (10 ml) and heated using microwave radiation at 120° C. for 2 hours. Purification of the reaction mixture by preparative HPLC (water/acetonitrile, 0.1% TFA) affords the title compound as the minor product of the reaction as the trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[O:15][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCOCC1c1ccc(F)c(F)c1
Reactant: O=C=NC(=O)Cl
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)COC2

Procedure:
3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Y(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Intermediate Y(3)). LC-MS (M+H)+=282.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.08-7.20 (m, 3 H) 4.67 (d, J=15.26 Hz, 1 H) 4.46 (dd, J=15.56, 2.14 Hz, 1 H) 3.98-4.10 (m, 2 H) 3.67 (br. s., 1 H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of salicylaldehyde (2 ml) in acetonitrile (20 ml) was added K2CO3 (5.71 g), followed by N-(2-choroethyl)morpholine hydrochloride (3.5 g) and then the mixture was stirred at room temperature for 2 hours, then at reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to afford 2-[2-(4-morpholinyl)ethoxy]benzaldehyde, as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[F:26])[N:34]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 2-fluoro-phenylhydrazine according to the method described for example 91.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([Cl:47])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][CH2:38][O:39][CH3:40])=[CH:27][C:26]=2[CH3:41])[CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:9]=1.Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([Cl:47])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][CH2:38][O:39][CH3:40])=[CH:27][C:26]=2[CH3:41])[CH2:16][NH2:17])=[CH:10][CH:9]=1
Reactant: COCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2′-(2-methoxyethyl)-3-methylbiphenyl-4-yl]propyl}carbamate from step 4 (1 eq.) in CH2Cl2 (0.06M) at room temperature was added HCl 4M in dioxane (30 eq.). The reaction mixture was stirred for 3 h at room temperature and then concentrated to dryness. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3 2M) 4%, afforded the title compound as a colorless oil. 1H NMR (400 MHz, acetone-d6): δ 7.46-7.20 (m, 6H); 7.22-7.12 (m, 2H); 7.07-6.97 (m, 3H); 6.81 (d, 2H); 4.39-4.32 (m, 4H); 3.60 (s, 3H); 3.55-3.45 (m, 2 H); 3.31-3.19 (m, 1H); 3.0-2.75 (m, 6H); 2.45 (t, 2H); 2.32 (s, 3H); 2.20 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)([N:10]1[CH:14]=[CH:13]N=[CH:11]1)=[O:9].Cl.N1CC[CH:24]([O:27][C:28]2[N:33]=[CH:32][N:31]=[C:30]([N:34]3[C:42]4[C:37](=[CH:38][C:39]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:41]=4)[CH2:36][CH2:35]3)[CH:29]=2)[CH2:23]C1>C1COCC1>[N:15]1([C:8]([N:10]2[CH2:11][CH2:23][CH:24]([O:27][C:28]3[N:33]=[CH:32][N:31]=[C:30]([N:34]4[C:42]5[C:37](=[CH:38][C:39]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])=[CH:40][CH:41]=5)[CH2:36][CH2:35]4)[CH:29]=3)[CH2:13][CH2:14]2)=[O:9])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
Triethylamine (286 μL, 2.05 mmol) and 1,1′-carbonyldiimidazole (249 mg, 1.54 mmol) were added to a THF (9.00 mL) solution of the 1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]-5-(propylsulfonyl)indoline hydrochloride (450 mg, 1.03 mmol) produced in Reference Example 32, and the mixture was stirred at room temperature for 3 hours. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, water was added, and the mixture was stirred. The deposit was collected by filtration and washed with water to obtain the title compound as white powder (291 mg, yield: 57%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[C:20]([N:24]1[CH:29]=[CH:28]C(=O)N=C1)([CH3:23])([CH3:22])[CH3:21].[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O.CCCCCC>[C:20]([N:24]1[CH2:29][CH2:28][CH:34]([CH:35]=[O:31])[CH2:33][CH2:32]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)n1ccc(=O)nc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)N1CCC(C=O)CC1
Reaction time: 0.5 h

Procedure:
6.52 g of diisopropylamine was dissolved in 24 mL of tetrahydrofuran, and the solution was cooled on ice. Then, 2.91 mL of n-butyl lithium (a 2.66 M hexane solution) was added thereto. After stirring at the same temperature for 30 minutes, the mixture was kept at −78° C. To the reaction mixture, 3.87 mL of trimethylsilyldiazomethane (a 2 M hexane solution) was added at the same temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a solution prepared by dissolving 1 g of 1-tert-butylpyrimidin-4-one (synthesized by the method as described in J. Org. Chem., 2005, 70, 1930) in 6 mL of tetrahydrofuran was added at the same temperature, and the mixture was stirred at the same temperature for 1.5 hours, and heated overnight under reflux. To the reaction mixture, water was added, and the mixture was extracted with 200 mL of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. Then, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 120 mL of ethyl acetate, and 24 g of silica gel was added thereto at room temperature. The mixture was stirred at the same temperature for 1.5 hours. The insolubles were filtered, and the filtrate was concentrated under reduced pressure to obtain 830 mg of 1-tert-butylpiperidin-4-carboaldehyde [87-1] (hereinafter, referred to as the compound [87-1]).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](Br)[CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:28](=[O:29])[CH2:27][N:26]([CH3:30])[C:25]2=[O:31])[CH:20]=[C:21]([Cl:23])[CH:22]=1.O>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:11][CH2:12][CH2:13][C@:27]32[N:26]([CH3:30])[C:25](=[O:31])[N:24]([C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=2)[C:28]3=[O:29])=[CH:6][CH:5]=1
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Reaction time: 30 h
Yield: 110.8 %

Procedure:
KOH flakes (1.3 g, 23.2 mmol) were added at RT to a solution of 1-bromo-4-(1,4-dibromobutyl)benzene (4.08 g, 10.6 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (2.5 g, 9.6 mmol, prepared according to Fujinami et al. cited above) in dry DMSO (40 ml). After 30 h at RT, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to yield an orange oil (4.98 g) which was chromatographed over silica gel (DCM/pentane 50/50) to give 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (2.1 g) as a white solid having the relative stereochemistry depicted above. 1H NMR (CDCl3): 7.45 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.03 (2H, d, J=8.4 Hz), 6.65 (2H, m), 3.36 (1H, dd, J1=12.9 Hz, J2=6.2 Hz), 3.13 (3H, s), 2.4-2.65 (1H, m), 1.8-2.4 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=CC(O)=[CH:5][CH:4]=1.[N+:10]([O-:13])(O)=[O:11].[C:14]([O:17][C:18](=[O:20])[CH3:19])(=O)[CH3:15]>C(O)(=O)C>[C:18]([O:17][C:14]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([N+:10]([O-:13])=[O:11])[CH:15]=1)(=[O:20])[CH3:19]
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc(OC(C)=O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 90 %

Procedure:
One mole of 4-methoxy-phenol in a mixture of 300 ml acetic anhydride and 300 ml acetic acid was refluxed for 12 hours. After cooling, 54 ml of nitric acid (1.3 equivalents, fuming nitric acid, d=1.52) was added dropwise at room temperature. The temperature rose to about 70° C. and nitrous vapors appeared. After completion of the addition the mixture was left under stirring for 2 hours to give 4-methoxy-3-nitrophenyl acetate as a precipitate. Isopropyl ether (300 ml) was added and the mixture was cooled to 0° C. The precipitated material was collected and dried, giving 190 g (yield=90%), m.p. 116° C.
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].Br[CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38]>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: FC(F)(F)CCCBr
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(CCCC(F)(F)F)C2=O)nc1C
Yield: 60 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 4-bromo-1,1,1-trifluorobutane instead of bromomethyl-2,2-difluorocyclopropane, the title compound was obtained as a yellow solid in 60% yield: mp 108-110° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.97 (t, J=9.0 Hz, 2H), 3.57-3.47 (m, 2H), 3.28 (t, J=9.0 Hz, 2H), 2.50 (s, 3H), 2.40 (s, 3H), 2.32-2.19 (m, 2H), 1.76-1.62 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 155.9, 155.8, MS (ES+) m/z 336.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1C(=O)N([Cl:31])C(=O)C1>>[Cl:31][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=2[CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)[NH:7][CH:6]=1
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1cc(C)c2[nH]cc(Cl)c2c1Cc1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized by a chlorination of 2-((5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile using NCS analogously to the preparation of Example 85. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (s, 1H) 11.29 (br. s., 1H) 7.98 (d, J=0.76 Hz, 1H) 7.75-7.87 (m, 1H) 7.61 (d, J=8.34 Hz, 1H) 7.44-7.55 (m) 7.39-7.44 (m) 6.86 (s, 1H) 4.75 (d, J=4.55 Hz, 2H) 2.42 (s, 3H) 2.24 (s, 3H). HRMS calcd. for C13H16ClN4 (M+H)+ 335.1058. found 335.1062.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[C:17]([CH3:23])=[N:18][C:19]([CH2:20][CH2:21][CH3:22])=[C:12]2[N:11]=1)[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[C:17]([CH3:23])=[N:18][C:19]([CH2:20][CH2:21][CH3:22])=[C:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3ccccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
1.64 g (5.25 mmol) of 2-(2-ethoxyphenyl)-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one (example VI) are added in portions to 3.14 ml of chlorosulfonic acid while cooling with ice. The reaction mixture is stirred at room temperature for 16 hours, then diluted with dichloromethane and poured onto ice water. The organic phase is washed with water and dried over magnesium sulfate and the solvent is removed in vacuo. 2.15 g (99%) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzene-sulfonyl chloride are obtained.
Reaction SMILES: ClC[S:3]([NH:6][CH2:7][C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:12][C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[N:10][N:9]1[C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:5])=[O:4].[SH:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].[C:43](=O)([O-])O.[Na+].O>CN(C=O)C>[C:38]([O:37][C:36](=[O:42])[NH:35][CH2:34][CH2:33][SH:32]([S:3](=[O:5])(=[O:4])[NH:6][CH2:7][C:8]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:9]([C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[N:10]=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[S:12]1)[CH3:43])([CH3:39])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCl)(c2ccccc2)S1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[SH](CCNC(=O)OC(C)(C)C)S(=O)(=O)NCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 39 %

Procedure:
N-[5-Chloromethanesulfonylaminomethyl-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro[1,3,4]thiadiazol-2-yl]-2,2-dimethylpropionamide (3.818 g, 7.807 mmol) obtained in Step 1 mentioned above was dissolved in DMF (70 mL), and tert-butyl N-(2-mercaptoethyl)carbamate (13.3 mL, 78.1 mmol) and saturated aqueous sodium hydrogencarbonate (15 mL) were added, then the mixture was stirred at 70° C. for 5.5 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=9/1→7/3), and then triturated with diisopropyl ether to give [2-({[3-(2,2-dimethylpropionyl)-5-(2,2-dimethyl-propionylamino)-2-phenyl-2,3-dihydro[1,3,4]thiadiazol-2-ylmethyl]sulfamoyl}-methylsulfanyl)ethyl]carbamic acid tert-butyl ester (1.926 g, 39%).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[C:5]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH2:12]>C1C=CC=CC=1>[CH2:10]1[C:5]2([O:12][CH2:4][CH:3]=[CH:2][CH2:1][O:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: C/C=C\C
Reactant: O
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Product: C1=CCOC2(CCCCC2)OC1

Procedure:
Cis-but-2-ene, 4-diol (50 g), cyclohexanone (50 g) and SNCA catalyst (2.5 g) were refluxed in benzene (75 ml) using a Deanstark water separator. The catalyst was filtered, the solvent evaporated and the residue distilled at 80°-85° C./4 torr to give 7,12-dioxaspiro[5,6]dodec-9-ene of formula III (92%) of the drawings.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:16]([O:20][C:21]([N:23]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:24]1[C:25]([C:31]2[O:35][N:34]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([C@@H:42]4[CH2:47][O:46][CH2:45][CH2:44][N:43]4[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:38][CH:37]=3)[CH:32]=2)=[N:26][C:27](Br)=[CH:28][N:29]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+].O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CC#N>[C:58]([O:57][C:55]([N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:24]1[C:25]([C:31]2[O:35][N:34]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([C@@H:42]4[CH2:47][O:46][CH2:45][CH2:44][N:43]4[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[CH:38][CH:37]=3)[CH:32]=2)=[N:26][C:27]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=2)=[CH:28][N:29]=1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc([C@@H]3COCCN3C(=O)OC(C)(C)C)cc2)no1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
A mixture of (4-isopropylsulfonylphenyl)boronic acid (892.7 mg, 3.914 mmol), tert-butyl (3R)-3-[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]morpholine-4-carboxylate (2.5 g, 3.558 mmol), Na2CO3 (3.558 mL of 2 M, 7.116 mmol), water (17.60 mL) and MeCN (25.00 mL) were degassed by vacuum/nitrogen cycles (3×) then Pd[P(tBu)3]2 (90.92 mg, 0.1779 mmol) was added and vessel flushed with nitrogen via vacuum/nitrogen cycles (2×). Mixture then heated at 50° C. (drysyn block temp) for 3 h. The reaction was cooled to rt, and then diluted with EtOAc (10 mL) and water (10 mL) and the organic layer separated and then washed with water (2×10 mL) and brine (1×10 mL), dried MgSO4, filtered and concentrated in vacuo. The crude product purified by ISCO (120 g SiO2, 0 to 50% EtOAc/petroleum ether) to leave product as a white foam (2.52 g, 88% yield)
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C)(C)C(O)/C=C/Br
Product: CCCCC(C)(C)C(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 1.88 g. (8 moles) of 1-bromo-4,4-dimethyl-trans-1-octen-3-ol (Example 1174) with 2.58 g. (8 moles) of triphenylmethyl bromide in 20 ml. of pyridine and purification of Florisil, all as described in Example 728 gives the title compound.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[CH3:22].[Cl:32]CCl>>[ClH:32].[CH:1]1([N:8]([CH:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:19][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([N:21]([CH3:22])[CH3:20])=[CH:24][CH:25]=2)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: ClCCl
Reactant: c1cc2c(c(NC3CCCCCC3)c1)CCCCC2
Product: CN(C)c1ccc(NC(=O)N(C2CCCCCC2)C2CCCCc3ccccc32)cc1
Product: Cl

Procedure:
N-Cycloheptyl-(6,7,8,9-tetrahydro-5H-benzocycloheptenyl)amine (0.8 g, 3.1 mmol) and 4-(N,N-dimethyamino)phenylisocyanate (0.50 g, 3.1 mmol) was stirred in dichloromethane (10 ml) at room temperature for 18 hrs. The reaction mixture was then purified by silica gel column chromatography. The resulting urea compound was treated with hydrochloric acid in ether to give 0.72 g of the above hydrochloride compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:17][N:18](C)C=O>O>[C:17]([C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(Br)ccnc12
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)c2c(C#N)ccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-5,8-dimethyl-6-nitroquinoline (3.87 g, 13.77 retool), cuprous cyanide (3.67 g, 41.31 mmol) and dimethylformamide (70 mL) is stirred at room temperature for 30 minutes and then heated to 155° C. and stirred at this temperature for 1 hour. Water is added, and the reaction mixture is filtered. The precipitate is washed with water and methylene chloride. The filtrate is extracted with methylene chloride (3×125 mL), and the combined organic layers are dried (sodium sulfate) and evaporated. Purification by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using chloroform as eluent, provides 4-cyano-5,8-dimethyl-6-nitroquinoline.