Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.O[C:36]1[CH:37]=[C:38]([CH:41]=C[CH:43]=1)[C:39]#[N:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:43]=[CH:36][CH:37]=[C:38]([C:39]#[N:40])[CH:41]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4cccc(C#N)c4)cc3)c2cc1OC
Yield: 6.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hydroxybenzonitrile (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (5 mg, yield 6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=O)=[CH:5][CH:4]=1.Cl.[CH3:14][NH:15][C:16](=NC)[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>>[CH3:14][N:15]1[C:16]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])=[N:10][N:9]=[C:7]1[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: C=CCCCC(=NC)NC
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Product: C=CCCCc1nnc(-c2ccc(OC)cc2)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.12 g yield starting from 4-methoxybenzhydrazide (0.5 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.48 g). MS (m/z): 258 [MH]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>O1CCCC1>[CH3:23][S:20]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[CH:8][CH:9]=1)(=[O:22])=[O:21]
Reactant: N#CC(=NO)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(C#N)c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)-4-bromobenzyl cyanide was prepared in the following manner. Thus, 81.0 g (0.36 mole) of α-hydroxyimino-4-bromobenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 49.0 g (0.43 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 103.0 g of a solid residue which was purified by repeating recrystallization from acetonitrile to give 81.8 g of a white crystalline product having a melting point of 128° C., which could be identified to be the target compound from the results of the analysis described below. The above mentioned yield of the product corresponds to 75.0% of the theoretical value.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[C:5]2[N:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][S:6]2.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[CH2:14]([O:13][C:11]([C:10]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[N:4][C:3]=1[CH2:2][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH3:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1c(CBr)nc2sccn12
Solvent: CC#N
Product: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Product: [Br-]

Procedure:
To a stirred suspension of Step 2 intermediate (1.90 g, 6.571 mmol) in acetonitrile (40 mL) was added triphenylphosphine (1.89 g, 7.228 mmol) at room temperature. The resulting reaction mixture was slowly heated to reflux overnight. The solvent was concentrated in vacuo and the residue was stirred with diisopropyl ether and filtered. The solid was dried under vacuum to afford 3.90 g of the product as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.2 Hz, 3H), 4.08 (q, J=6.9 Hz, 2H), 5.35 (s, 1H), 5.40 (s, 1H), 7.20-7.22 (m, 1H), 7.37 (br s, 1H), 7.50 (d, J=4.5 Hz, 1H), 7.68-7.76 (m, 10H), 7.81-7.87 (m, 3H), 7.99 (d, J=3.9 Hz, 1H); ESI-MS (m/z) 471.24 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C:11](=O)[CH2:10]2.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[C:2]1([NH:1][CH:11]2[CH:12]3[CH2:15][CH2:16][N:9]([CH2:14][CH2:13]3)[CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: c1ccc(NC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(Method 1A) To a mixture of 9.3 g (0.1 mol) of aniline and 16.1 g (0.1 mol) of 1-azabicyclo[2.2.2]octan-3-one hydrochloride in 250 mL of dichloroethane (DCE) was added 31.8 g (0.15 mol) of Na(OAc)3BH and the mixture was stirred overnight at room temperature. The reaction was quenched with 3 N NaOH. The layers were separated and the aqueous layer was extracted with an additional portion of CHCl3. The organic layers were combined, dried over NaSO4, and then filtered and the solvent was evaporated in vacuo. Th residue was chromatographed on silica (95/5 CHCl3/10% NH4OH in MeOH) to give N-Phenyl-1-azabicyclo[2.2.2]octan-3-amine (6.0 g 30%) as an off-white solid. MH+=203. 1H NMR (CDCl3) 1.46 (m, 1H), 1.75 (m, 3H), 2.0 (m, 1H), 2.55 (m, 1H), 2.95 (m, 4H), 3.4 (m, 2H), 3.8 (s, 1H), 6.6 (d, 2H), 6.75 (t, 1H), 7.2 (t, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>C([O-])(O)=O.[Na+]>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:32]4[CH2:33][O:30][CH2:31]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C1COC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C2COC2)C3)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (ca) (1.0 g, 2.5 mmol), 3-oxetanone (0.91 mL, 13 mmol) and sodium triacetoxyborohydride (1.7 g, 8.1 mmol) in 1,2-dichloroethane (25 mL, 320 mmol) was stirred at 70° C. under N2 for 3 h. The mixture was then cooled down and poured in diluted NaHCO3. The organic and aqueous phases were separated. The aqueous phase was extracted with 2×50 mL of DCM. The combined organic phases were dried with Magnesium sulfate, filtered and concentrated. The crude solid was purified by flash chromatography (100% DCM to 5% MeOH/DCM) to provide product ih as a pale yellow solid: 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 6.15 (s, 1H), 4.64 (t, J=6.5 Hz, 2H), 4.55 (d, J=5.9 Hz, 2H), 4.13 (d, J=6.7 Hz, 1H), 3.87 (d, J=11.4 Hz, 1H), 3.62 (dd, J=34.1, 22.2 Hz, 6H), 3.43 (d, J=16.1 Hz, 2H), 3.20-3.04 (m, 2H), 2.69 (d, J=4.6 Hz, 3H), 1.24 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS: m/z=+453 (M+H)+.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=O)[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].Cl.CN(C=O)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:15])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
BOC-Thr(Bzl)-OH (32.88 g, 0.15 M) was dissolved in THF (100 ml). HOBT (20.94 g, 0.155 M) and H-Pro-OBzl.HCl (37.47 g, 0.155 M) were added thereto, and DMF (200 ml) was added to prepare a solution. WSCI (28.37 ml, 0.155 M) was added dropwise during 10 minutes while cooling with a freezing mixture, then the mixture was stirred at room temperature overnight. The solvent was distilled off in vacuo. Ethyl acetate (500 ml) was added to the residue, which was then washed with 5% aqueous sodium bicarbonate (twice), saturated sodium chloride solution, 1 N HCl (twice), saturated sodium chloride (twice) and water, in that order. After drying with anhydrous sodium sulfate, the solvent was distilled off and the mixture was concentrated in vacuo to obtain oil substance [5] (57.41 g, yield: 77.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13].Cl[S:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42])(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42])(=[O:24])=[O:23])[C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13]
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2OC)c2ccc(Cl)cc21
Yield: 86.2 %

Procedure:
This compound is prepared according to the procedure described in step A of EXAMPLE 28 from 6 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-indol-2-one and 6.66 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. 10.3 g of the expected product are obtained after crystallization from iso ether.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.[C:27]([O-])(=O)[CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([O:16][CH2:29][C:28]4[CH:27]=[CH:9][C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2c(O)cccc2n1Cc1ccc(Cl)cc1
Reactant: CCC(=O)[O-]
Product: CC(C)(Cc1cc2c(OCc3ccc4ccccc4n3)cccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title product was prepared according to conditions described in Steps D and E of Example 1 substituting methyl 3-[N-(p-chlorobenzyl)-4-hydroxy indol-2-yl]-2,2-dimethylpropanoate for the propanoate in Example 1 (Step D), m.p. 158°-160° C. Anal. C, H, N: Calc. C 72.20; H 5.45; N 5.61 Found C 72.25; H 5.60; N 5.75.
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[C@H:4]([CH2:11][OH:12])[CH2:3]1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[OH:12][CH2:11][C@H:4]1[N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:6][C@H:2]([S:1][C:19](=[O:21])[CH3:20])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)N1C[C@H](S)C[C@H]1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)S[C@@H]1C[C@@H](CO)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
To a solution of (2S,4R)-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-yl)-methanol (0.28 g) in dichloromethane (10 ml) were added pyridine (0.131 g) and acetic anhydride (0.160 g). The reaction mixture was stirred for 4 h at room temperature, treated with ice/water and extracted with EtOAc. The organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:2 as eluent to obtain thioacetic acid (3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester (0.080 g) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23]CC)=[O:22])[C:9]=2[S:26][CH3:27])=[CH:4][CH:3]=1.O[Li:29].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O-:23])=[O:22])[C:9]=2[S:26][CH3:27])=[CH:4][CH:3]=1.[Li+:29]
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1SC
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CSc1c(C(=O)[O-])nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: [Li+]

Procedure:
To a magnetically stirred solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate (4.9 g, 11 mmol) in tetrahydrofuran (100 ml) was added LiOH.H2O (0.47 gram, 11 mmol) and the resulting mixture was reacted for 20 hours at 35° C. and subsequently concentrated in vacuo. The obtained crude lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate was used in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([O:26][CH3:27])=[C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[CH:13]=2)[N:8]([C@H:28]([C:32](C)(C)[O:33][SiH2]C(C)(C)C)[CH:29]([CH3:31])[CH3:30])[CH:7]=1)=[O:5])C.C(O)(C)C.[OH-].[Na+]>CCCCCCC>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:26][CH3:27])[N:8]([C@H:28]([CH2:32][OH:33])[CH:29]([CH3:31])[CH3:30])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn([C@@H](C(C)C)C(C)(C)O[SiH2]C(C)(C)C)c2cc(OC)c(Cc3cccc(Cl)c3F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCCC
Product: COc1cc2c(cc1Cc1cccc(Cl)c1F)c(=O)c(C(=O)O)cn2[C@H](CO)C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (900 mg) was added to isopropyl alcohol (3.6 mL), and 1N sodium hydroxide (3.6 mL) was added. After stirring at 70° C. for 3 hr, the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled, and allowed to cool to room temperature. n-Heptane (5 mL) was added and, after stirring, the mixture was partitioned. The aqueous layer was washed with n-heptane (5 mL). 35% Hydrochloric acid (400 mg) was added to the aqueous layer, methylisopropylketone (10 mL) was added and, after stirring, the mixture was partitioned. The organic layer was washed successively with 8.5% aqueous sodium hydrogencarbonate solution (5 mL) (3 times), 0.5N hydrochloric acid (5 mL) containing sodium chloride (250 mg), and 10% brine (5 mL). After the washing, methylisopropylketone was evaporated under reduced pressure to give 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (680 mg, yield 99.3%) as a yellow-white solid.
Reaction SMILES: [O:1]=[C:2]([C:14]1[S:21][C:20]([CH3:22])=[C:19]2[C:15]=1[CH2:16][C@H:17]1[C:23]([CH3:25])([CH3:24])[C@H:18]12)[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1>C(O)C.C1COCC1.[Pd]>[O:1]=[C:2]([C:14]1[S:21][C:20]([CH3:22])=[C:19]2[C:15]=1[CH2:16][C@H:17]1[C:23]([CH3:25])([CH3:24])[C@H:18]12)[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: Cc1sc(C(=O)C=Cc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(C(=O)CCc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzoic acid (780 mg, 2.21 mmol), Pd/C (250 mg, 10% Pd) in ethanol (50 mL) and THF (10 mL) is stirred at rt for 2 h under 1.5 bar H2. The reaction mixture is filtered, the filtrate is evaporated and the crude product is purified by CC on silica gel eluting with EA to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-benzoic acid (751 mg) as a colourless foam; LC-MS: tR=1.04 min, [M+1]+=355.08; 1H NMR (CDCl3): δ 8.02 (d, J=7.6 Hz, 2H), 7.32 8d, J=7.6 Hz, 2H), 3.12-2.90 (m, 5H), 2.77 (d, J=18.8 Hz, 1H), 2.37 (s, 3H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.69 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([NH2:50])[CH:44]=1>C(Cl)(Cl)Cl>[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[C:45]([NH:50][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH3:7])[CH:10]=2)[CH:44]=1
Reactant: CCCN(CCC)Cc1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1cccc(C(=O)Nc2cc(C(=O)OC)ccc2N)c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
The compound (300 mg) obtained in Example 18-2, WSCI hydrochloride (365 mg), and HOBt (260 mg) were dissolved in chloroform (6.0 ml), and the whole was stirred for 1 hour. Then, 3,4-diaminobenzoic acid methyl ester (198 mg) was added thereto and the whole was stirred for 2 hours. A solid was precipitated, so DMF (2.0 ml) was added thereto and stirring was continued for additional 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a saturated ammonium chloride aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (381 mg) as a brown oily substance.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH:25]([CH3:34])[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH3:35][O:36]C(Cl)=O>ClCCl>[CH3:34][C:25]1[N:2]([CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]2)[C:35](=[O:36])[O:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cl
Reactant: NC1CCN(CCc2ccccc2)CC1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)oc(=O)n1C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 5.4 %

Procedure:
To a solution of a 4-amino-1-phenethyl-piperidine hydrochloride (Example 8c, 2 g, 0.0072 Mol) and triethylamine (3.31 ml, 3.3 Mol eq) in dichloromethane (30 ml) was added 2-bromopropiophenone (1.54 g, 1 Mol eq) and the reaction mixture was stirred for 14 h at room temperature. After ice-bath cooling, methylchloroformate (3.36 ml, 6 Mol eq) was added and the reaction mixture stirred for a further 1 h. Triethylamine (5 ml) was added and the reaction mixture was concentrated in vacuo. The residue was redissolved in methanol (50 ml) and sodium methoxide (3 g) was added. After stirring at room temperature for 0.5 h, the reaction mixture was heated under reflux for 1h. After cooling, the solution was concentrated under vacuum and the residue obtained was partitioned between dichloromethane and water then dried (MgSO4), filtered and evaporated. The crude product was purified on a silica gel column using 0 to 2% methanol in dichloromethane as eluent then recrystallised from diethyl ether/hexane to give the title compound as a colourless solid (0.14 g, 5%). Mp 144° C. 1H NMR (DMSO) δ 1.72 (2H, m), 2.08 (2H, m), 2.30 (3H s), 2.33 (2H, m), 2.50 (2H, m), 2.75 (2H, m), 3.04 (2H, s), 3.69 (1H, m), 7.16-7.33 (5H, m), 7.42-7.47 (5H, m); MS (CI) m/e 363 [MH]+. Anal. Found C, 76.10; H, 7.19; N, 7.61. C23H26 ClN3O. 0.35H2O requires C, 76.21; H, 7.23; N, 7.73%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][CH:42]=[C:16]23)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:43][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][C:42]([F:43])=[C:16]23)[CH2:13][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2ccnn12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2c(F)cnn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.76 g) in acetonitrile (15 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.1 g), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.24 g, 13%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]([CH3:27])[N:21]=[CH:20]4)C)=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])[CH3:2].ClC1C=CC2N(C(CC3C=C4C(=CC=3F)N(C)N=C4)=CN=2)N=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH2:15][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]([CH3:27])[N:21]=[CH:20]4)=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])[CH3:2]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Product: C=C(OCC)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound 68.3 from 6-chloro-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine.