Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C:23]12[CH2:31][CH:30]1[CH2:29][CH:28]1[CH:24]2[CH2:25][NH:26][CH2:27]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH:28]3[CH:24]([C:23]4([NH2:22])[CH:30]([CH2:29]3)[CH2:31]4)[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NC12CC1CC1CNCC12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC3CC4CC4(N)C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 5 %

Procedure:
5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (298 mg, 1.0 mmol) was added to a solution of 1-amino-4-azatricyclo[6.1.0.02,6]nonane (206 mg, 1.36 mmol) and triethylamine (418 μl, 3.0 mmol) in acetonitrile (10 ml) at room temperature, and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the acetonitrile was evaporated. To the residue was added an aqueous hydrochloric acid solution, followed by washing with chloroform. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and washed with chloroform. The aqueous layer was adjusted to pH 7.5 with an aqueous hydrochloric acid solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from ethanol. Recrystallization from 2-propanol gave 21 mg of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][NH:26]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH2:32]=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][N:26]5[CH3:32])[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC[C@H]2CCCN2)n1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC[C@@H]1COc1cccc(Cn2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)n1

Procedure:
2-(4-Chlorophenyl)-6-({6-[(2R)-pyrrolidin-2-ylmethoxy]pyridin-2-yl}methyl)thieno[2,3-d]pyridazin-7(6H)-one (0.340 g, 0.75 mmol), formaldehyde(aq.) 36% (0.23 mL, 2.25 mmol) and MacroPorous-triacetoxyborohydride (0.88 g, 2.25 mmol) were shaked in DCM/MeOH (1:1, 4 mL) at room temperature for 3 hours. The reaction mixture was filtrated, concentrated in vacuo and purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.01) in n-heptane, which gave the product as an solid. Yield: 0.207 g (59%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.55-7.61 (m, 2H), 7.37-7.48 (m, 4H), 6.69 (d, 1H, J=7.27 Hz), 6.59 (d, 1H, J=8.26 Hz), 5.45 (s, 2H), 4.21-4.27 (m, 1H), 4.06-4.14 (m, 1H), 2.97-3.04 (m, 1H), 2.41-2.52 (m, 1H), 2.34 (s, 3H), 2.11-2.21 (m, 1H), 1.78-1.91 (m, 1H), 1.54-1.78 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 163.7, 157.4, 153.9, 152.3, 140.3, 139.2, 136.6, 136.0, 133.3, 131.4, 129.8, 128.2, 118.9, 114.3, 110.0, 68.3, 64.4, 57.9, 56.0, 41.8, 28.7, 23.1. MS (ESI+) 467.0 (M+1H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:38]([NH:35][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[C:7]2=[O:20])=[CH:23][CH:24]=1)(=[O:37])=[O:36])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Yield: 75 %

Procedure:
The reaction of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) with benzoyl chloride was carried out according to the method of Example 13, Step C. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) provided a 75% yield of the title compound as white crystals, mp 91°-93° C.; satisfactory purity by TLC 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 673 (M+K)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18](OC)=[O:19])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>O1CCCC1>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: COC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A suspension of 0.76 g of lithium aluminum hydride in 10 mL of tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. To the suspension was added dropwise a solution of 2.18 g of methyl 1,4-dioxaspiro[4.5]decane-8-acetate in 10 mL of tetrahydrofuran, followed by stirring at room temperature for 3 hours. After the reaction mixture was cooled to 0° C., 1 mL of water was added thereto. The mixture was filtered through celite and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.73 g of 1,4-dioxaspiro[4.5]decane-8-ethanol represented by the following formula:
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.C([Li])CCC.[CH:27](N1CCCCC1)=[O:28]>C1COCC1>[CH:27]([C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1C=O
Temperature: -72 °C
Yield: 68.4 %

Procedure:
A solution of 1D (1.75 g, 5 mmol) in dry THF (50 mL) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 4 mL, 10 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional hour. N-formyl piperidine (1.1 mL, 10 mmol) was added, and then the reaction was allowed to warm up to 0° C. and maintained there for an hour. The solution was quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 5 min, extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-30%) in hexane to give the title compound as a yellow solid (1.02 g, 68%). LC/MS (method A): retention time=4.24 min, (M+H-tBu)+=243. 1H NMR (CDCl3, 400 MHz): δ 10.25 (s, 1H), 10.15 (s, 1H), 8.86 (d, J=9.0 Hz, 1H), 8.00-8.02 (m, 2H), 7.87(d, J=9.0 Hz, 1H), 7.38-7.47 (m, 3H) 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 197.93, 153.16, 151.18, 138.26, 138.14, 136.51, 129.45, 129.27, 127.50, 126.78, 125.80, 82.03, 28.64.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:14]([C:18]1[C:19]([Cl:27])=[C:20]([C:24](O)=[O:25])[N:21]([CH3:23])[N:22]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:24]([C:20]2[N:21]([CH3:23])[N:22]=[C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:19]=2[Cl:27])=[O:25])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6-bromo-3-nitro-pyridin-2-ylamine (750 mg, 3.44 mmol) in THF (20 mL) was treated with NaH (413 mg, 10.3 mmol) at room temperature for 1 h. Simultaneously a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (969 mg, 4.47 mmol, prepared as described in Example B) in DCM (20 mL) was treated with oxalyl chloride (390 μL, 4.47 mmol) and DMF (4 drops) at room temperature for 1 h. The acid chloride solution was concentrated to dryness in vacuo, taken up in THF (10 mL), and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted twice with EtOAc (60 mL, 20 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 1 min, then 1:99 to 3:17 v/v over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 10.48 (br. s., 1H), 8.31 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 4.12 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C14H15BrClN5O3: 416.0 (M+H). Measured: 416.1.
Reaction SMILES: S.[S].[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[S:8]([O-:12])([O-:11])(=[O:10])=[S:9].[NH3:13]>>[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[NH4+:13].[NH4+:13].[S:8]([O-:12])([O-:11])(=[O:10])=[S:9].[NH4+:13].[NH4+:13]
Reactant: N
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: S
Product: [NH4+]

Procedure:
A process is provided for the removal of hydrogen sulfide out of a gaseous stream (22), such as a natural gas, by contacting the hydrogen sulfide containing gas with a sorbing liquid (26) containing a tertiary amine so that the hydrogen sulfide is sorbed into the liquid in absorber (11) and transferring the sorbing liquid/hydrogen sulfide mixture to a reactor (15) where the tertiary amine promotes the conversion of the hydrogen sulfide into polysulfide via reaction with sulfur; transferring the polysulfide solution from the reactor (15) to a regenerator (10) where polysulfide is converted into elemental sulfur via reaction with air (9); transferring at least a portion of the solution (25) containing elemental sulfur, as well as sulfate and thiosulfate species, into a mixture (36) where it is contacted with gaseous ammonia which reacts with the sulfate and thiosulfate species to produce ammonium sulfate and ammonium thiosulfate which are removed from the solution while the remaining portion of solution (25) is transferred to a sulfur recovery unit (14). That portion of the solution which has been subjected to ammonium sulfate and ammonium thiosulfate removal is rejoined with that portion of the solution (25) being forwarded to sulfur recovery unit (14). The solution from the sulfur recovery unit (14) is recycled back to the absorber (11).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[C@:24]3([N:28]([CH3:29])[C:27](=[O:30])[N:26]([C:31]4[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=4)[C:25]3=[O:39])[CH2:23][N:22]([CH2:40][C:41]3[S:45][CH:44]=[C:43]([C:46]([OH:48])=O)[CH:42]=3)[CH2:21]2)=[CH:16][CH:15]=1)#[N:13].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@:24]3([N:28]([CH3:29])[C:27](=[O:30])[N:26]([C:31]4[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=4)[C:25]3=[O:39])[CH2:23][N:22]([CH2:40][C:41]3[S:45][CH:44]=[C:43]([C:46]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:48])[CH:42]=3)[CH2:21]2)=[CH:18][CH:19]=1)#[N:13]
Reactant: CS(N)(=O)=O
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)NS(C)(=O)=O)cs1)C[C@H]2c1ccc(C#N)cc1
Reaction time: 48 h
Yield: 34.2 %

Procedure:
EDCI (84 mg, 0.44 mmol) was added to a solution of Example 37 (100 mg, 0.18 mmol), methanesulfonamide (38 mg, 0.38 mmol), triethylamine (62 μl, 0.43 mmol) and a trace of DMAP in DCM (5 ml) at room temperature. After 48 h, water was added and the mixture was acidified by bubbling SO2. The organic layer was separated and the aqueous layer extracted twice with DCM. The combined organic layers were washed with brine and concentrated in vacuo. The resulting product was chromatographed over silica gel to yield the above-titled compound (38.9 mg) as an amorphous solid along with 55.6 mg of unreacted starting material. 1H NMR (CDCl3): 8.04 (1 H, s), 7.62 (2H, d, J=8 Hz), 7.40 (1H, s), 7.25-7.3 (3H, m), 6.65 (2H, d, J=1.5 Hz), 3.8-4.1 (3H, m), 3.86 (3H, s), 3.3-3.4 (2H, m), 3.3.25 (3H, s), 3.15-3.3 (1H, m), 3.01 (1H, d, J=11 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Mg+2].O1CC[CH2:46][CH2:45]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][NH:12][CH:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:45][CH3:46])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: C1CCOC1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Cl)C2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(NCCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
2-(5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide (40 mg, 0.0873 mmol) was added to lithium aluminum hydride (4.3 mg, 0.104 mmol) in tetrahydrofuran (1 mL) at 0° C., and the resulting reaction solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was mixed with water, ethyl acetate and anhydrous magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (chloroform/methanol=13/1) to give the desired product (9.5 mg, 25% yield).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 4-iodobenzonitrile (10.0 g), copper(I) iodide (166 mg), triphenylphosphine (572 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (904 mg), propargyl alcohol (2.83 ml), diisopropylethylamine (30.5 ml) and tetrahydrofuran (170 ml) was stirred at room temperature for 23 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-67:33) to give the object product (5.79 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[CH2:9])[N:5]=[CH:4][N:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: C=C(OCC)c1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
4-Chloro-6-[1-(ethyloxy)ethenyl]pyrimidine (Intermediate 17, 3.54 g, 19.17 mmol) was dissolved in acetone (177 mL), treated with 2M aqueous hydrochloric acid solution (28.8 mL, 57.5 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was neutralised with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a white solid (2.30 g);
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1cc(C=O)cn1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2cnn(C)c2)cc1
Reaction time: 120 h
Yield: 41.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 4-formyl-1-methylpyrazole (0.4 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 5 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethanol:ethyl acetate 1:3→1:2) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-4-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 87) (96.1 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:27]1([OH:33])[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2([O:32][CH:29]3[CH2:30][CH2:31][CH:27]([OH:33])[CH2:28]3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1CCc1ccccc1
Reactant: OC1CCC(O)C1
Product: O=C1c2ccccc2C(OC2CCC(O)C2)(c2ccc(Cl)cc2)N1CCc1ccccc1

Procedure:
3-Chloro-3-(4-chlorophenyl)-2-phenethylisoindolin-1-one (256 mg, 0.687 mmol) was reacted with 1,3-cyclopentanediol (0.32 mL, 3.44 mmol.) as for general procedure F and the solvent evaporated under vacuum to leave a clear oil of 3-(4-chlorophenyl)-3-(3-hydroxycyclopentyloxy)-2-phenethylisoindolin-1-one. This was purified by HPLC (76.0 mg, 0.170 mmol., 25%). Rf 0.13 (40:60 EtOAc:petrol). IR: 2359, 1958, 1684, 1601, 1491, 1464 cm−1. 1H NMR (300 Hz, CDCl3); δ 0.95-2.04 (m, 6H, cyclopentanediol C—H), 2.24 (m, 1H, N—CH2—CH2—Ar), 2.81 (m, 1H, N—CH2—CH2—Ar), 3.19 (m, 1H, N—CH2), 3.42 (m, 1H, N—CH2), 3.70-3.83 (m, 1H, HO—C—H), 4.32 (m, 0.5H, C—O—C-h), 4.43 (m, 0.5H, C—O—C—H), 6.95-7.23 (m, 11H, Ar), 7.45 (m, 2H, Ar), 7.81 (m, 1H, Ar). 13C NMR (75 Hz, CDCl3); δ 31.7, 31.9, 32.2, 33.7, 33.9, 34.0, 34.6, 32.7, 35.2 (cyclopentane C), 41.6, 41.7, 41.8, 42.0, 42.1, 43.7, 44.1, 45.7, 50.9 (N—CH2—CH2) 72.3, 72.6, 73.0, 73.2, 73.9, 74.0 (cyclopentane C—O), 94.6, 94.7 (quaternary O—C—N), 123.0, 123.8, 123.9, 124.1, 124.2, 126.8, 128.1, 128.3, 128.4, 128.5, 128.9, 129.0, 129.1, 129.2, 129.2, 130.4, 130.4, 130.4, 132.8, 133.1, 134.9, 137.8, 137.8, 138.3, 139.3, 146.3, 146.3, 149.1 (Ar), 168.4, 168.6, 168.7 (C═O). LC/MS-ES+ m/z 480.2, 478.1, 458.1, 456.1, 293.0. Anal. Calcd. for C28H22ClNO3.0.25H2O: C, 73.04; H, 4.93; N, 3.04%. Found C, 73.24; H, 5.00; N, 3.22%. HRMS (EI) m/z: 455.1288. Found 455.1297.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:24]=3[Cl:34])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37]>Cl.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:35])[C:23]3[CH:28]=[C:27]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:26]=[CH:25][C:24]=3[Cl:34])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:36]([F:37])([F:38])[F:39]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cc(-n2cccn2)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1cc(-n2cccn2)ccc1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 85 °C

Procedure:
4-Chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide from step 5 was dissolved in a mixture of 4 M HCl in dioxane (8 mL) and water (2 mL) and heated at 85° C. for 2 h. The solvent was evaporated and the residue was purified via HPLC to give 4-chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: 1H NMR (400 MHz, CDCl3) δ 8.2 (m, 3H), 8.0 (m, 1H), 7.9 (s, 1H), 7.7 (m, 4H), 7.45 (d, 1H), 6.45 (s, 1H); MS m/z: 576.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH:10]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1c1ccc(N2CCC(N3CCC(O)CC3)C2)c(F)c1

Procedure:
According to Method J1, 2-[3-fluoro-4-(3-oxo-pyrrolidin-1-yl)-phenyl]-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one was reacted with piperidin-4-ol. In this way the product was obtained with molecular weight 509.63 (C29H36FN3O4); MS (ESI): 510 (M+H+).