Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][CH:8]=1>>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(CO)n1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(CCl)n1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (13.8 ml) was added over ˜15 minutes to a stirred solution of ethyl 6-(hydroxymethyl)-2-pyridinecarboxylate (28.5 g) in MDC (200 ml) maintaining the temperature at 10-15° C. using an ice-water bath. On completion of the addition the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue partitioned between toluene (200 ml)/saturated bicarb (sodium bicarbonate solution, 200 ml). The layers were separated and the organic phase washed with water (150 ml). The solvent was evaporated to leave a pale oil which solidified on standing. (31.3 g).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[N:31]([CH2:35][CH:36]([O:38][C:39](=[O:41])[CH3:40])[CH3:37])[N:30]=1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:33]=[C:32]([CH3:34])[N:31]([CH2:35][CH:36]([O:38][C:39](=[O:41])[CH3:40])[CH3:37])[N:30]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: CC(=O)OC(C)Cn1nc(N)cc1C
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(=O)OC(C)Cn1nc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)cc1C

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and acetic acid 2-(3-amino-5-methyl-pyrazol-1-yl)-1-methyl-ethyl ester (Intermediate 98) afforded acetic acid 2-{3-[2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-5-methyl-pyrazol-1-yl}-1-methyl-ethyl ester as a mixture of diastereomers (180 mg, 39%); ES+-HRMS m/e calcd for C27H31N5O6F2 [M+H+] 560.2315 found 560.2313. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.45 (m, 4H), 1.17, 1.18 (2×d, J=6.4 Hz, 3H), 1.45-1.58 (m, 2H), 1.77-1.92 (m, 1H), 1.94, 1.95 (2×s, 3H), 2.22 (s, 3H), 3.09-3.28 (m, 2H), 3.73-3.86 (m, 2H), 3.97-4.14 (m, 2H), 5.01-5.18 (m, 1H), 5.53 (dd, J=10.7, 3.2 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 6.21 (s, 1H), 7.33-7.43 (m, 2H), 7.44-7.54 (m, 1H), 8.29 (d, J=2.3 Hz, 1H), 10.75, 10.77 (2×s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[CH:22]=1.[Cl:23]Cl>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[C:22]=1[Cl:23]
Reactant: ClCl
Reactant: C[C@@H]1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Product: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O
Temperature: 0 °C

Procedure:
4 g (0.011 M) of (S)-7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 35 ml of ice-cold concentrated hydrochloric acid at -10° C. and chlorine gas is conducted in at -10° C. for 1 hour. The mixture is concentrated at 0°-5° C. using a high vacuum cooling trap and a soda lime tower under a high vacuum (1-2 mmHg). The residue is made alkaline with a mixture of ice and 10% sodium bicarbonate solution. The mixture is extracted with methylene chloride and the extract is dried over sodium sulphate, filtered and concentrated. The remaining oil is purified on a 300 g silica gel column using methylene chloride and then methylene chloride/ethyl acetate (20:1) as the eluting agent. This operation is repeated once on a 120 g silica gel column using methylene chloride and then methylene chloride/ethyl acetate (20:1) as the eluting agent. After crystallisation from ethyl acetate/ether, there is obtained (S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one which melts at 222°-226° C.; [α]25D =+92° (in methylene chloride; 0.5%).
Reaction SMILES: [C:1]1([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].O>CCOCC>[CH2:14]([CH:6]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: C(=Nc1ccncc1)c1cccs1
Solvent: CCOCC
Solvent: O
Product: CCCCC(Nc1ccncc1)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.2 %

Procedure:
To a stirred, cooled (10°-20° C.) solution of 3,77 grams of 4-(2-thenylideneamino)pyridine in 100 milliliters of dry ether, a solution containing 0.025 mole butyl lithium in 50 milliliters of dry ether was added dropwise. The resulting solution was stirred at room temperature for 4 hours, and then diluted with 150 ml dry ether before cautious addition of 50 ml. water. The organic phase was dried (MgSO4) and evaporated to dryness to give 5.24 grams of a brown oil. This brown oil was dissolved in toluene and extracted with 2N hydrochloric acid. The extracts were basified with sodium hydroxide and extracted back into toluene. The resulting solution of the base in toluene was dried (MgSO4) and evaporated to dryness. The resulting oil was crystallised from petrol (100°-120° C.)/toluene affording 2.0 grams of a white solid. This material was dissolved in isopropanol and converted to the hydrochloride salt with ethereal hydrogen chloride and crystallised by addition of ether, yielding 1.153 grams of N-[α-butyl-2-thenyl]-4-pyridinamine hydrochloride of melting point 146.5°-148° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37]>ClC(Cl)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:8]=2[N:7]2[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([Cl:42])=[C:33]([Cl:32])[CH:34]=3)=[N:4][N:5]=[C:6]2[CH2:12][N:11]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)c1ccc(Cl)c(Cl)c1)CN=C2c1ccccc1Cl
Reaction time: 1 h
Yield: 65 %

Procedure:
9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (0.28 g) and triethylamine (0.115 ml) were dissolved in dichloroethane (15 ml). 3,4-Dichlorobenzoyl chloride (0.17 g) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as a developing solvent. The obtained solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.27 g of N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:5]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:6]([CH:14]=[C:15](/[CH:18]=[N:19]/[CH2:20][CH2:21][OH:22])[C:16]=1[F:17])[C:7]([NH:9][O:10][CH2:11][CH2:12][OH:13])=[O:8]>CO>[F:3][C:4]1[C:5]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:6]([CH:14]=[C:15]([CH2:18][NH:19][CH2:20][CH2:21][OH:22])[C:16]=1[F:17])[C:7]([NH:9][O:10][CH2:11][CH2:12][OH:13])=[O:8]
Reactant: O=C(NOCCO)c1cc(/C=N/CCO)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NOCCO)c1cc(CNCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 8 h

Procedure:
Sodium borohydride was added to a solution of the imine, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[(E)-2-hydroxy-ethylimino]-methyl}-benzamide obtained in Step A in MeOH at 0° C. While being allowed to warm gradually, the mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue was purified with a silica gel column (CH2Cl2:MeOH (4:1 to 2:1)) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=2[O:16][CH3:17])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[CH:22]=[CH:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][C:22]3[C:23]4[C:28](=[N:27][CH:26]=[CH:25][CH:24]=4)[NH:20][CH:21]=3)=[CH:10][C:9]=2[O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccc(Cl)cc1
Reactant: c1cnc2[nH]ccc2c1
Product: COc1cc(Cc2c[nH]c3ncccc23)ccc1OCc1ccc(Cl)cc1

Procedure:
Additional compounds were prepared using the protocol of Scheme 33, Steps 2 and 3, replacing 4-(4-chlorobenzyloxy)-3-methoxybenzaldehyde 106 with a suitable aldehyde (prepared as described in Example 34), and optionally replacing 1H-Pyrrolo[2,3-b]pyridine 94 with an appropriate substituted 7-azaindole (see Example 9 or Example 16) in Step 2. The following compounds were made following this procedure:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1F.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 16.5 %

Procedure:
2,5-Difluorobenzoic acid methyl ester (25 g, 145 mmol), piperazine-1-carboxylic acid tert-butyl ester (27 g, 145 mmol) and K2CO3 (50 g, 363 mmol) are added to 1,4-dioxane and the mixture is heated to 110° C. for 2 days. The reaction mixture is cooled, inorganic salts filtered through sintered funnel and filtrate is concentrated under reduced pressure. Crude compound is purified by column chromatography (silica-gel, 100-200 mesh, eluent; 5% EtOAc in hexane) to afford desired 4-(4-fluoro-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a syrupy liquid (8.1 g, 16.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:42])([F:41])[C:26]1[N:31]=[CH:30][C:29]([CH2:32][O:33][C:34]2[CH:39]=[N:38][NH:37][C:36](=[O:40])[CH:35]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:37]3[C:36](=[O:40])[CH:35]=[C:34]([O:33][CH2:32][C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:41])[F:42])=[CH:27][CH:28]=4)[CH:39]=[N:38]3)[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cn[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.13 g, 0.34 mmol), 5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (0.10 g, 0.67 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (15 mg, 0.10 mmol) and copper iodide (0.16 g, 0.84 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 48 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL) and washed with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes) gave the title compound (46 mg, 24%) as an orange film: 1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 5.41 (s, 2H), 4.59-4.57 (m, 2H), 3.68-3.64 (m, 5H), 3.01-2.98 (m, 2H), 1.97-1.90 (m, 2H), 1.36-1.27 (m, 9H).
Reaction SMILES: [CH2:1]([C:3]1([S:6]([O:9]CCCC)(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].[S-]C#N.[K+:17]>O1CCOCC1.O>[CH2:1]([C:3]1([S:6]([O-:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].[K+:17]
Reactant: CCCCOS(=O)(=O)C1(CC)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCC1(S(=O)(=O)[O-])CC1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a solution of butyl 1-ethylcyclopropane-1-sulfonate (0.46 g, 2.23 mmol prepared from Preparation #6 Step A and ethyl iodide using KKK) in 1,4-dioxane (2.79 mL) and water (2.79 mL) was added potassium thiocyanate (0.12 mL, 2.23 mmol). The reaction is heated to about 100° C. for about 16 h. The reaction mixture was cooled to ambient temperature and was concd under reduced pressure to afford potassium 1-ethylcyclopropane-1-sulfonate (0.42 g, 100%) as a white crystalline solid: 1H NMR (400 MHz, DMSO) d 1.70-1.58 (m, 2H), 0.89 (t, J=7.5, 3H), 0.80 (q, J=3.8, 2H), 0.32 (q, J=3.8, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1O>>[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[O:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Oc1ccc2ccccc2c1Br
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc2ccccc2c1Br

Procedure:
The same method as in Example 38 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 1-bromo-2-naphthol instead of 8-hydroxyquinoline to give the objective compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)=[CH:3][CH:2]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][N:12]=1
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Reactant: Cc1[nH]cnc1CSCCN
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccncc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (5.9 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (4.3 g) was heated at 145°-150° for 5 hours and allowed to cool to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. This residue was triturated with water, and treated with ethanolic hydrogen chloride to give the title compound m.p. 228°-233°.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=O.[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]>>[C:7]([C:9](=[C:2]([CH:4]1[CH2:6][CH2:5]1)[CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)C1CC1
Product: CCOC(=O)C(C#N)=C(C)C1CC1
Yield: 27.9 %

Procedure:
A solution of 118 g (1.4 mol) of cyclopropyl methyl ketone and 113 g (1 mol) of ethyl cyanoacetate was reacted by a method similar to Example 3a) to give 50 g (yield 29%) of ethyl 2-cyano-3-cyclopropylbut-2-enoate (b.p. 105° C./6 mbar).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]CC)=[O:24])[N:21]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[OH:31][C@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[CH2:29][NH:28][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)Cn1nnc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)n1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(-c4nnn(CC(=O)O)n4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from ethyl {5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetate (which was obtained in Example 48) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedures of Example 98 and Example 99 as a white solid; mp>240° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.65 (m, 2 H), 1.90–2.10 (m, 2 H), 2.50–3.10 (m, 5 H), 2.95 (s, 3 H), 3.65–3.85 (m, 2 H), 4.89 (brd, J=8.3 Hz, 1 H), 5.08 (d, J=15.9 Hz, 1 H), 5.15 (d, J=15.9 Hz, 1 H), 6.88 (d, J=8.3 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.09 (dd, J=8.3, 2.0 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.87 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 532.1 (MH+); HRMS Calcd. for C21H30N7O4S (MH+): 532.1973. Found: 532.1965.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)=[O:27])[CH:21]=1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C3(C)CCOCC3)cc2)n1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 486 (M++1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[OH:17].[OH-].[Na+].O>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[O:17][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: CCN1CC2OC2C1
Reactant: Oc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Oc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.10 mole) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g. (0.11 mole) of 2,6-dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and wahed with three 50-ml. portions of 5% sodium hydroxide an one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatogrpahed on silica gel to give 12.9 g. (47%) of and oil residue. The oil was converted to the hydrchloride and recrystallized from isopropyl alcohol-diethyl ether to yield 12.3 g. (39%), m.p. 160°-162° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH3:10])[N:12]=2)[C:3](=[O:9])[NH:4][N:5]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: Cn1ccc(N)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2cc(Cl)n[nH]c2=O)n1
Temperature: 100 °C
Yield: 25.5 %

Procedure:
To a mixture of 4-bromo-6-chloropyridazin-3(2H)-one (838 mg, 4.0 mmol), 1-methyl-1H-pyrazol-3-amine (427 mg, 4.4 mmol), tris(dibenzylideneacetone)di-palladium(0) (91.6 mg, 0.1 mmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropy-lbiphenyl, 97% (170 mg, 0.4 mmol) in 1,4-dioxane (12 mL) was added sodium tert-butoxide (845.7 mg, 8.8 mmol). The mixture was purged with nitrogen and sealed in a pressure tube. The reaction mixture was heated at 100° C. overnight. The mixture was cooled to room temperature, and filtered through Celite®. The filtrate was concentrated. The residue was purified on silica eluted with a gradient of 0 to 3.5% methanol in methylene chloride with 1% ammonium hydroxide to afford 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)pyridazin-3(2H)-one (109g) (230 mg, 25%).
Reaction SMILES: [CH2:1]=[C:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([Cl:13])[C:6]=1[Cl:14])=[O:4]>S(=O)(=O)(O)O>[CH3:1][CH:2]1[CH2:15][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:3]1=[O:4]
Reactant: C=C(C)C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 2-methylene-2',3'-dichloro-4'-methoxypropiophenone (40 g., 0.163 mole) in concentrated sulfuric acid (75 ml.) is allowed to stand at 25°C. for 24 hours and then is slowly poured into vigorously stirred ice water (500 ml.). The 2-methyl-5-methoxy-6,7-dichloro-1-indanone (VI) which separate (40 mg.) melts at 129°C. after recrystallization from methylcyclohexane.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: BrCCCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCCc3ccccc3)C2=O)cn1
Yield: 36 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and (3-bromopropyl)benzene. Yield: 36%. MS M+H calculated 394.2; found 394.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.26 μM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[BH4-].[Li+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ncc(Br)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-3-fluoropyridine-2-carbonyl chloride (0.50 g, 2.1 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0° C. and treated with lithium borohydride (1.0 mL, 2 M tetrahydrofuran solution, 2.1 mmol, 1 equiv). After stirring for 30 minutes at 0° C., the mixture was treated with methanol (2 mL) and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.