Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[ClH:1].[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]2(=[O:23])=[O:22])=[CH:16][CH:17]=1
Reactant: CN
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)cc1
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(F)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(4-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (50 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(4-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (46 mg):
Reaction SMILES: CC(C)([O-:4])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([S:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23]([CH:27]=O)=[CH:22][CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>>[CH2:33]([O:32][C:31](=[O:4])[CH:30]=[CH:27][C:23]1[C:24]2[C:19](=[CH:18][C:17]([S:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=3)(=[O:16])=[O:15])=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:29]
Reactant: O=Cc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Product: CCOC(=O)C=Cc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium tert-butoxide (6.5 mL of 1M THF solution) was added dropwise to 1.3 mL of triethylphosphonyl acetate (6.5 mmol) at 0° C. This solution was then added dropwise to a room temperature solution of 6-(3-Fluoro-benzenesulfonyl)-naphthalene-1-carbaldehyde (1.7 g, 5.4 mmol) in 100 mL THF. The reaction mixture was stirred for 18 hours at room temperature, then quenched with dilute aqueous HCl. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 2.1 g of crude 3-[6-(3-fluoro-benzenesulfonyl)-naphthalen-1-yl]-acrylic acid ethyl ester, which was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]2[S:55][C:56]([Cl:59])=[CH:57][CH:58]=2)=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:59][C:56]1[S:55][C:54]([CH2:53][O:52][C:49]2[CH:48]=[CH:47][C:46]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:51][CH:50]=2)=[CH:58][CH:57]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc(OCc2ccc(Cl)s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCc5ccc(Cl)s5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-[(5-chloro-2-thienyl)methoxy]phenyl borate (186 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed at 100° C. for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give 7-[4-[(5-chloro-2-thienyl)methoxy]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 104) (137 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10]3)[CH:16]=1
Reactant: N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
(S)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.16 mmol, 50 mg) was dissolved in THF (2 mL) and triethylamine (0.299 mmol, 42 μL, 30 mg) followed by methanesulfonyl chloride (0.16 mmol, 18.4 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (S)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)methanesulfonamide (32.1 mg, 0.082 mmol, 51.2%) MS (ESI): m/z [M+H]+ 390.0
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:28]3[CH2:29][CH2:30][CH2:31][NH:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCCNC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCCNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-3-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, J=8 Hz, 1 H), 7.99 (s, 1 H), 7.89-7.87 (q, J=7.2 Hz, 1 H), 7.73-7.68 (q, J=14 Hz, 2 H), 7.62-7.55 (m, 2 H), 6.14 (s, 1 H), 5.36 (s, 2 H), 4.58-4.51 (m, 2 H), 4.34 (s, 1 H), 3.75 (s, 2 H), 3.63-3.60 (d, J=11.6 Hz, 1 H), 3.47-3.44 (m, 1 H), 3.07-3.02 (d, J=11.6 Hz, 2 H), 2.47 (s, 3 H), 2.17-2.14 (m, 2 H), 2.05-2.00 (m, 1 H), 1.85-1.84 (m, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.C(N(CC)CC)C.C1(C(Cl)=O)C2C(=CC=CC=2)C=CC=1.[F:32][C:33]([F:62])([F:61])[C:34]1[CH:35]=[C:36]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=1)=[O:38]>ClCCl.O>[F:62][C:33]([F:32])([F:61])[C:34]1[CH:35]=[C:36]([CH:54]=[C:55]([C:57]([F:58])([F:59])[F:60])[CH:56]=1)[C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:41][C@@H:40]1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=1)=[O:38]
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: Cc1ccc(C[C@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C(Cl)c1cccc2ccccc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@H]2CN(C(=O)/C=C/c3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a stirred mixture of trans-3-(3-pyridyl)acrylic acid (100 mg) and triethylamine (0.19 ml) in dichloromethane (10 ml) was added 1-naphthoyl chloride (0.1 ml) at -15° C. After stirring for 30 minutes, a solution of (2S)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (300 mg) in dichloromethane (10 ml) was added at -15° C. and the resulting mixture was stirred for 30 minutes at the same temperature and then for 1 hour at room temperature. Dichloromethane and water were added to the reaction mixture and the organic layer was separated, washed successively with aqueous saturated sodium bicarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified on a silica gel column (20 g) eluting with a mixture of dichloromethane and methanol (100:2) to give (2S)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl benzyl)-4-[3-(3-pyridyl)-trans-acryloyl]piperazine (0.34 g).
Reaction SMILES: ClCC[CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[Cl-:19].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[Cl:19][CH2:4][CH2:5][C:6]([C:15]1[CH:16]=[CH:17][C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=1)=[O:7]
Reactant: c1ccc2ccccc2c1
Reactant: [Cl-]
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCCl)c1ccc2ccccc2c1
Yield: 38.3 %

Procedure:
2-chloroethylpropionyl chloride (2.78 g), naphthalene (2.56 g), and aluminium chloride (3.2 g) were reacted in nitrobenzene (9 mL) at 0° C., followed by treatment with hydrochloric acid to obtain the title compound (1.5 g).
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOC)(=O)C.[C:13]([O:16][C@:17]1([C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27](=[CH:28][C:29](=[O:39])[CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O>[C:13]([O:16][C@:17]1([C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[C:27](=[CH:28][C:29](=[O:39])[CH2:30][CH2:31]2)[C:26]([CH3:1])=[CH:25]3)[CH2:22][CH2:21]1)[C:18](=[O:20])[CH3:19])(=[O:15])[CH3:14]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: COCOC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 70 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A suspension of 0.5 g of sodium acetate in 60 ml of anhydrous chloroform and 2 ml of distilled phosphorus oxychloride is refluxed under agitation for 30 minutes at a bath temperature of 70° C. After adding 15 ml of methoxymethyl acetate and 2.0 g of 17α-acetoxy-4-pregnene-3,20-dione, the reaction solution is further stirred for 5 hours at 70° C. Subsequently such an amount of a saturated soda solution is added dropwise at room temperature that the aqueous phase remains alkaline. The organic phase is separated, washed with water, and dried over sodium sulfate. After concentration, the crude product is purified on 100 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 1.26 g of 17α-acetoxy-6-methyl-4,6-pregnadiene-3,20-dione, mp 217°-219° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24]>C(#N)C>[C:4]([OH:25])(=[O:8])/[CH:5]=[CH:15]/[C:17]([OH:20])=[O:19].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g (89%). A small sample (1.67 g) was dissolved in ethanol and treated with I equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g, m.p.=142°-143° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:80]2[CH:84]=[N:83][C:82]([O:85][CH2:86][CH2:87][O:88][C:89]3[CH:90]=[C:91]([CH2:95][NH2:96])[CH:92]=[CH:93][CH:94]=3)=[N:81]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:96][CH2:95][C:91]2[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH2:87][CH2:86][O:85][C:82]3[N:83]=[CH:84][NH:80][N:81]=3)[CH:90]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:19]1=2
Reactant: CCOC(=O)c1nc2scc(-c3cccs3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3cccs3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-(2-thienyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 39 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (149 mg, 46%).
Reaction SMILES: [C:1]1([C:7]2[C:12]([F:13])=[CH:11][C:10]([O:14]CC3C=CC=CC=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(OCC)(=O)C.[OH-].[Na+]>[Pd].C(O)(=O)C>[F:13][C:12]1[CH:11]=[C:10]([OH:14])[CH:9]=[N:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cc(OCc2ccccc2)cnc1-c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1cnc(-c2ccccc2)c(F)c1
Reaction time: 3 h
Yield: 77 %

Procedure:
6.55 g (29.7 mM) of 2-phenyl-3-fluoro-5-(phenylmethoxy)pyridine are added to 160 ml of methanol, 30 ml of ethyl acetate and 30 ml of acetic acid. 0.33 g of 10% palladium-on-charcoal is added. The mixture is stirred under a hydrogen atmosphere for 3 hours. The catalyst is filtered off and the solvents are concentrated to give a white solid, which is taken up with 1 N sodium hydroxide solution. The aqueous phase obtained is washed with dichloromethane and then acidified to pH 5 with 1 N hydrochloric acid solution. The white precipitate obtained is filtered off and washed with water. After drying, the desired product is obtained in the form of a white solid with a yield of 77%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=[CH:11][CH:12]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][N:15]([CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:26][C:27]([NH2:29])=[O:28])[CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)CCl
Reactant: Fc1cccc(COc2cccc(CCNCc3ccco3)c2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CN(CCc1cccc(OCc2cccc(F)c2)c1)Cc1ccco1
Yield: 99.3 %

Procedure:
A solution of 1.8 g (5.53 mmol) of [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine, 0.57 g (6.08 mmol) of 2-chloro-acetamide and 0.92 ml (6.62 mmol) of triethylamine in 5 ml of dry dimethylformamide was heated at 120° C. for 2 hours with microwaves. Solvent was removed under vacuum, water was added and the product was extracted with ethyl acetate. The crude reaction mixture was purified by flash chromatography (dichloromethane/methanol 95:5 v:v). 2.1 g (99% yield) of a yellow oil were isolated.
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[C:13]2[C:12]([C:14]3[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=3)=[N:11][NH:10][C:9]=2[C:8](=[O:22])[N:7]1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:33]=[CH:32][O:31][N:30]=2)=[CH:25][CH:24]=1)[CH2:4][CH3:5])[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]([CH:6]1[C:13]2[C:12]([C:14]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=3)=[N:11][NH:10][C:9]=2[C:8](=[O:22])[N:7]1[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:33]=[CH:32][O:31][N:30]=2)=[CH:27][CH:28]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)C1c2c(-c3ccc(OC)nc3)n[nH]c2C(=O)N1c1ccc(-c2ccon2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CC)C1c2c(-c3ccc(=O)[nH]c3)n[nH]c2C(=O)N1c1ccc(-c2ccon2)cc1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a mixture of 4-(1-ethylpropyl)-5-(4-isoxazol-3-ylphenyl)-3-(6-methoxypyridin-3-yl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.067 g, 0.15 mmol) and sodium iodide (0.067 g, 0.45 mmol) in acetonitrile (3 mL) was added chlorotrimethylsilane (0.058 mL, 0.45 mmol). The mixture was heated under reflux with stirring for 1 h. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture, and the precipitate was collected by filtration and dried to give 4-(1-ethylpropyl)-5-(4-isoxazol-3-ylphenyl)-3-(6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (0.041 g, 64%) as slightly yellow crystals.
Reaction SMILES: [F:1]C(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13](F)[C:12]([C:16]2([C:36]#[N:37])[CH:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:19][CH:18]([C:26]([OH:28])=O)[CH:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[C:11]([F:38])[CH:10]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:26]([CH:18]1[CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:16]([C:12]2[CH:13]=[C:14]([F:1])[C:9]([Cl:8])=[CH:10][C:11]=2[F:38])([C:36]#[N:37])[CH:20]([CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[NH:19]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)OC[C@H](CCN)O1
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
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1cc(F)c(Cl)cc1F
Yield: 64.4 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 108c (0.5 g, 0.84 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.73 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 50%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[S:23][C:22]([CH2:24][CH2:25][C@@H:26]([NH:38]C(=O)OC(C)(C)C)[CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)=[N:21][N:20]=1)=[CH:14][CH:13]=2>C(Cl)Cl>[NH3:10].[F:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[S:23][C:22]([CH2:24][CH2:25][C@@H:26]([NH2:38])[CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=3)=[N:21][N:20]=1)=[CH:14][CH:13]=2
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: N[C@H](CCc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 164.4 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl (R)-4-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (85 mg, 155 μmol) in DCM (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting yellow oil was purified by reversed phase HPLC (Shimadsu Valiant, Phenomenex Gemini C18 5 μm 100×30 mm, 5% to 50% H2O/MeCN, 0.1% TFA) to deliver a colorless oil. The oil was dissolved in MeOH, absorbed onto ISOLUTE Si-TsOH(SCX-3) (5 g), and washed with MeOH (50 mL) and then with 2 N NH3 in MeOH (30 mL) providing (2R)-4-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-amine (57 mg, 82%) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.88-2.16 (m, 2 H), 2.85 (d, J=13.6, 7.6 Hz, 1 H), 3.02 (dd, J=13.6, 5.8 Hz, 1 H), 3.15-3.28 (m, 1 H), 3.34-3.49 (m, 2 H), 7.53 (s, 1 H), 7.76 (d, J=8.0 Hz, 1 H), 7.95 (d, J=8.0 Hz, 1 H), 8.15 (dd, J=8.7, 1.3 Hz, 1 H), 8.23 (d, J=8.7 Hz, 1 H), 8.45 (s, 1 H), 8.63 (s, 1 H), 9.05 (s, 1 H). LCMS (API-ES) m/z: 470.0 (M+Na+).
Reaction SMILES: CS([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([CH3:16])[CH2:10]2)[S:6][N:5]=1)=O.[CH3:17][CH:18]([OH:22])[C:19]#[C:20][CH3:21].[H-].[Na+]>CN(C)C=O.COC(C)(C)C>[CH3:17][CH:18]([O:22][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([CH3:16])[CH2:10]2)[S:6][N:5]=1)[C:19]#[C:20][CH3:21]
Reactant: CC1CC(C)CN(c2nc(S(C)=O)ns2)C1
Reactant: CC#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC#CC(C)Oc1nsc(N2CC(C)CC(C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
In 3 ml of N,N-dimethylformamide were dissolved 287 mg of 3-methylsulfinyl-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole and 103 mg of 3-pentyn-2-ol, and 58 mg of sodium hydride (oil suspension; content: 60 weight %) was added under ice-cooling. The mixture was stirred for 15 minutes and at room temperature for 1.5 hour. Furthermore, 30 mg of sodium hydride (oil suspension; content: 60 weight %) and 100 mg of 3-pentyn-2-ol were added in the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with tert-butyl methyl ether, and extracted with tert-butyl methyl ether after the addition of water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 297 mg of 3-(1-methyl-2-butynyloxy)-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole (hereinafter, referred to as the present compound (21)).