Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a mixture of ethyl 2-(4-(benzyloxy)-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.00 g, 2.9 mmol) and anhydrous Cs2CO3 (1.12 g, 5.84 mmol) in DMF (10 mL) was added 2-chloropyrazine (0.40 g, 3.5 mmol). The reaction mixture was stirred at 90° C. for 1 h and quenched by addition of water (15 mL). The resulting mixture was extracted by EtOAc and the combined organic layers were washed with water (20 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil (0.74 g, Yield: 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][O:20]CC2C=CC=CC=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][OH:20])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
5% Pd/C (1.85 g, 50% wet) is added to a solution of 4-benzyloxymethylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (1.85 g, 0.0049 mol) in ethanol (20 mL). The reaction mixture is stirred under the positive pressure of hydrogen gas for 16 hrs at room temperature. The reaction mixture is filtered through celite bed and washed with a solution methanol and dichloromethane (1:5, 100 mL). Combine filtrate is concentrated under reduced pressure to give 4-hydroxymethylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]3[CH:14]=[CH:13][N:12](COCC[Si](C)(C)C)[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:2]1.[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].N12CCCN=C1CCCCC2>C(#N)C>[CH2:23]([S:25]([N:28]1[CH2:29][C:30]([CH2:32][C:33]#[N:34])([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[C:7]4[CH:14]=[CH:13][NH:12][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:2]2)[CH2:31]1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(CC#N)(n2ccc(-c3ncnc4[nH]ccc34)c2)C1
Reaction time: 4 h

Procedure:
A solution of 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.100 g, 0.318 mmol) and [1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile (0.118 g, 0.636 mmol, prepared as in Example 68) in acetonitrile (1 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (24 μL, 0.16 mmol). The mixture was stirred for 4 hours. The solvent was evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, then extracted with two further portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. The crude product was stirred with 25% TFA/DCM (8 mL) overnight. The solvents were evaporated. The product was then stirred with ethylenediamine (0.3 mL) in methanol (5 mL). Preparative HPLC-MS (eluting with a gradient of methanol and water containing 0.15% NH4OH) was used to purify the product. 1H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 7.54 (dd, 1H), 7.27 (d, 1H), 6.95 (dd, 1H), 6.82 (dd, 1H), 6.74 (d, 1H), 4.49 (d, 2H), 4.15 (d, 2H), 3.24 (s, 2H), 3.02 (q, 2H), 1.33 (t, 3H); LCMS (M+H)+: 371.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24]C2CCCCO2)[CH:18]([F:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31]C2CCCCO2)[CH2:12][C@@H:11]1O.[N+](=C)=[N-].C1(C)C=CC(S([Cl:52])(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:24])[CH:18]([F:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:31])[CH2:12][C@H:11]1[Cl:52]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(F)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: C=[N+]=[N-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(F)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 1.2 g of (5Z,13E)-(9S,11R,15R,16RS)-9-hydroxy-16-fluoro-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoic acid methyl ester (prepared from the corresponding acid in methylene chloride with 0.5-molar diazomethane solution at 0° C.), 800 mg of p-toluenesulfonic acid chloride, and 4 ml of pyridine is agitated for 16 hours at 0° C., then for 48 hours at 25° C. The mixture is worked up according to Example 1. Yield: 1.45 g of the 9-tosylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CS(C)=O.O.CCOCC>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C(F)(F)F
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CN1CCC2(CC1)CN(c1ccccc1C(F)(F)F)c1cc(Cl)ccc12
Reaction time: 0.5 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], 0.5 g of sodium hydride and 6 g of 2-fluorobenzotrifluoride in 30 ml of dimethylsulfoxide is stirred under nitrogen for 30 minutes. An exothermic reaction occurs during this time. Thereafter, the mixture is diluted with water, and the diluted mixture thrice with ether. The combined ether extracts are extracted with 2 N hydrochloric acid. The acidic extracts are basified providing a colorless oil. The oil is dissolved in ether and the solution is dried. The product is passed through an alumina column, ether eluant, to provide a colorless oil which is converted, in ether. to its maleic acid salt. The salt is recrystallized from an acetone-ether mixture to provide white platelets, mp 209°-211° C. of 6-chloro-1-(2-trifluoromethylphenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
3-(3,5-Dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (5.6 g), 4-fluoro-2-trifluoromethylbenzonitrile (4.5 g) and potassium carbonate (5.4 g) were added to N,N-dimethylformamide (50 mL), and the mixture was stirred at 110° C. for 4 hours. After cooling the mixture to room temperature, the solution was diluted with ethyl acetate and washed with water three times. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a column chromatography to obtain the title compound (3.8 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:42][CH:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:45][CH2:44]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
2.00 g (12.0 mmol) of benzyloxyacetic acid was dissolved in 40 mL of dichloromethane and 2.77 g (14.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2.21 g (14.4 mmol) of 1-hydroxybenzotriazole 1 hydrate, 2.52 mL (18.1 mmol) of triethylamine and 2.52 g (13.2 mmol) of 4-amino-1-benzylpiperidine were added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 18 hours. Dichloromethane was added to the reaction mixture and the mixture was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: ethyl acetate/methanol=100/0-90/10) to obtain 2.82 g (yield: 69%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([SH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]I)[CH:26]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC>[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][S:11][C:6]3[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=3[CH2:8][CH2:9][CH3:10])[CH:26]=2)[CH:19]=1
Reactant: COC(=O)c1cccc(Cc2cccc(CI)c2)c1
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCc1c(SCc2cccc(Cc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Yield: 84.9 %

Procedure:
Stir a mixture of 1-(2-Hydroxy-4-mercapto-3-propyl-phenyl)-ethanone (132 mg, 0.63 mmol), 3-(3-Iodomethyl-benzyl)-benzoic acid methyl ester (230 mg, 0.63 mmol), and cesium carbonate (410 mg, 1.26 mmol) in 2-butanone (6 ml) at room temperature under argon for 20 hours. Pour the mixture into water (60 ml) and extract with ethyl acetate (2×30 ml). Combine the organic extracts and wash with water, brine, then dry over sodium sulfate, filter and concentrate. Purify the crude product via silica chromatography eluting with 1:4 ethyl acetate:hexanes to give the title compound (240 mg, 85%). MS (m/z) 447 (M−H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16]>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1ccccn1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(C=Cc2ccccn2)cc1
Yield: 45.6 %

Procedure:
A mixture of 20.4 g (0.2 mol) acetic acid anhydride, 18.6 g (0.2 mol) 2-methylpyridine and 26.2 g (0.2 mol) 4-cyanobenzaldehyde is heated to reflux for 24 h. One allows to cool, mixes with excess ether and filters. One isolates 18.8 g of title compound (46% of theory) of the m.p. 98°-98° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.[C:53]1([C:59]2[N:63]=[C:62]([N:64]3[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[S:61][N:60]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:67]2[CH2:68][CH2:69][N:64]([C:62]3[S:61][N:60]=[C:59]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:63]=3)[CH2:65][CH2:66]2)=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 5.8 %

Procedure:
To a solution of a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1; 150.0 mg; 0.38 mmol; 1.0 eq.) in DMF (1.5 mL) was added 3-phenyl-5-piperazino-1,2,4-thiadiazole (93.2 mg; 0.38 mmol; 1.0 eq.) and the resulting reaction mixture was stirred at RT for 14 h. An aqueous solution of HCl (1N) was added and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered and evaporated to give an oil. This residue was taken up in CD3OD. The precipitate was filtered off and the mother liquids were evaporated and the resulting residue was then purified by chromatography (SiO2, gradient from 2/1 to 1/1 c-hex/EtOAc in about 30 min) to give the title product as a colorless oil (10 mg; 5.8%). M+(ESI): 459.0. HPLC (Condition A): Rt: 4.5 min (HPLC purity: 98.5%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28].CO>C(Cl)Cl>[Cl:24][CH2:25][CH2:26][C:27]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)CCCl)CC2)cc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
1-(4-Methoxyphenyl)piperazine dihydrochloride (1.85 g, 6.976 mmol) was dissolved in methylene chloride. After adding triethylamine (1.9 mL, 13.952 mmol) dropwise at 0° C. and then dissolving, the mixture was stirred for 30 minutes. After adding 3-chloropropionyl chloride (0.67 mL, 6.976 mmol), the reaction solution was stirred at room temperature for 1 hour. After adding methanol, the reaction solution was extracted with methylene chloride. The organic layer was dried with desiccant and then filtered. The filtrate was concentrated and purified by column chromatography (EtOAc/hexane, 4:1). A target compound (1.76 g, 6.224 mmol, 89.3%) was yielded as white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH:5]2[CH2:10][N:9]([C:11]3[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH2:8][C:6]2([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])[N:7]=1.CO.[ClH:37].C(OCC)C>C(=O)=O.ClCCl>[ClH:37].[NH2:1][C:2]1[S:3][CH2:4][C@@H:5]2[CH2:10][N:9]([C:11]3[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH2:8][C@:6]2([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])[N:7]=1
Reactant: NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)CC2CS1
Agent: Cl
Agent: O=C=O
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 38 %

Procedure:
Racemic N-[3-[2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide (451 mg, 929 μmol) is chirally purified by SFC (Column: Chiralcel OD-H (5 um), 2.1×25 cm; eluent: 40% methanol (0.2% isopropylamine) in CO2; flow 70 mL/min at UV 225 nm). Chiral analysis of the first eluting isomer: Column: Chiralcel OD-H (5 μm), 4.6×150 mm; eluent: 40% methanol (0.2% isopropylamine) in CO2; flow 5 mL/min at UV 225 nm confirms the enantiomerically enriched (>99% ee) enantiomer with Rt=1.01 minutes (175 mg, 360 μmoles). This material (free base, isomer 1) is dissolved in dichloromethane (1 mL) and methanol (0.5 mL) and 1 M hydrogen chloride in diethyl ether (0.36 mL, 360 μmoles) is added. The solvent is removed in vacuo to give the title compound (183 mg, 38%). ES/MS (m/e): 486 (M+H).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9]>CN(C=O)C.CCOC(C)=O>[C:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])#[N:3]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(C#N)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
A mixture of copper (I) cyanide (510 mg, 5.69 mmol) and DMF (16 mL) was heated to 140° C. The reaction was added methyl 3-bromo-4-methylbenzoate (505 mg, 2.2 mmol) in DMF (10 mL) and heating was continued for 12 h. The reaction was cooled, diluted with EtOAc (125 mL) and washed with H2O (5×25 mL). The EtOAc layer was dried over MgSO4 and concentrated. The residue was chromatographed (40 g silica, 10% EtOAc/hexanes) to give the title compound as a solid (236 mg, 61%); IR(CHCl3): 1128, 1269, 1300, 1725, 2231, 3024 cm−1; NMR(300 MHz, CDCl3): 2.63 (s, 3H); 3.95 (s, 3H); 7.43 (d, 1H, J=8.1 Hz); 8.14 (d, 1H, J=8.1 Hz); 8.28 (s, 1H); MS(FD): 175.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[N:18]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:17][C:3]1[C:2]([NH:1][NH2:18])=[CH:15][C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])=[C:5]([F:16])[CH:4]=1
Reactant: Nc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 50015.5 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using N-(5-amino-4-chloro-2-fluorobenzyl)-2,2,2-trifluoroacetamide (2.0 g, 0.007 mmol), NaNO2 (0.612 g, 0.008 mmol), SnCl2.2H2O (4.10 g, 0.018 mmol), and conc. HCl (100 mL) to afford 1.0 g of the desired product.
Reaction SMILES: [CH2:1](N1CC(C)(C)NCC21CCCC2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][C:22]([NH2:27])([CH2:25][CH3:26])[CH2:23][CH3:24].[CH3:28][C:29]([CH3:33])(O)[C:30]#N>>[CH2:1]([N:20]1[CH2:21][C:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[NH:27][CH2:28][C:29]1([CH3:33])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C#N
Reactant: CCC(N)(CC)CN
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Product: CCC1(CC)CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-5,5-diethyl-2,2-dimethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 3-(aminomethyl)pentane-3-amine and acetone cyanohydrin.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.CN(C)[CH:25]=[O:26].[CH3:28][OH:29]>>[CH3:28][O:29][C:25]([C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1)=[O:26]
Reactant: CO
Reactant: Brc1ccc2c(c1)CCc1ncccc1-2
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CCc1ncccc1-2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A flask charged with 8-bromo-5,6-dihydro-benzo[f]quinoline (4.00 g), triethylamine (3.0 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.63 g), N,N-dimethylformamide (5 mL), and methanol (20 ml) is flushed with argon for 5 min and with carbon monoxide for another 5 min. The mixture is then heated to 80° C. under carbon monoxide atmosphere (4 bar) and shaken at this temperature overnight. After cooling to room temperature, the mixture is filtered and concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to afford the title compound as a solid. Yield: 3.16 g (86% of theory); LC (method 1): tR=2.18 min; Mass spectrum (ESI+): m/z=240 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[CH2:1]([NH:11][C:26]([C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 5.4 ml (0.027 mol) of decylamine and 5.6 ml (0.04 mol) of triethylamine in 20 ml of methylene chloride cooled in an ice bath was added dropwise a solution of 5.0 g (0.027 mol) of 4-nitrobenzoyl chloride in 40 ml of methylene chloride. The reaction mixture was stirred in the ice bath for 30 minutes, at room temperature for 15 minutes and kept at 0° for 18 hours. After dilution with methylene chloride, the mixture was washed with 0.5N NaOH and the extract was dried and concentrated to a solid. Recrystallization from methylene chloride-hexane gave 8.1 g (98% yield, mp 89°-91°) of 4-[(decylamino)carbonyl]nitrobenzene. The nmr was consistent with the structure.
Reaction SMILES: ClC1C=C(C)C(C)=CC=1.[Mn]([O-])(=O)(=O)=[O:11].[K+].NC1C=CC(C)=C(N2[C:28](=[O:29])[C:27]3=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=[C:26]3[C:25]2=[O:35])C=1.[OH2:36]>>[Cl:34][C:31]1[CH:30]=[C:27]([C:28]([OH:29])=[O:11])[C:26](=[CH:33][CH:32]=1)[C:25]([OH:35])=[O:36]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(N)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: O
Agent: Cc1ccc(Cl)cc1C
Agent: [K+]
Product: O=C(O)c1ccc(Cl)cc1C(=O)O

Procedure:
The starting material is prepared as follows: The mixture of 9.0 g of 4-chloro-o-xylene and the solution of 60.7 g of potassium permanganate in 280 ml of water is refluxed until the purple color disappears (about 7 hours) whereupon 3/4 of the water are distilled off and the remaining suspension is filtered while still hot. The residue is washed with hot water several times, the clear and colorless filtrate (pH~12) is concentrated to about 50 ml and acidified with 33 ml of concentrated hydrochloric acid. The cold mixture is extracted 3 times with ethyl acetate, the organic layer dried and evaporated to give the 4-chlorophthalic acid.