Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]1[CH2:18][C:19]3([CH2:29][C:13]=1[CH:12]=2)[C:27]1[C:22](=[N:23][CH:24]=[CH:25][CH:26]=1)[NH:21][C:20]3=[O:28].CN1CCOCC1.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44]>C(Cl)Cl.CN1CCOCC1>[F:33][C:31]1[CH:30]=[C:4]([CH:3]=[C:2]([F:1])[CH:32]=1)[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]1[CH2:18][C:19]3([CH2:29][C:13]=1[CH:12]=2)[C:27]1[C:22](=[N:23][CH:24]=[CH:25][CH:26]=1)[NH:21][C:20]3=[O:28])[C:43](=[O:44])[C:42]([CH3:47])([CH3:46])[CH3:41]
Reactant: O=C1Nc2ncccc2C12Cc1cc3cc(CNCc4cc(F)cc(F)c4)cnc3cc1C2
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)C(=O)N(Cc1cc(F)cc(F)c1)Cc1cnc2cc3c(cc2c1)CC1(C3)C(=O)Nc2ncccc21
Temperature: 0 °C
Reaction time: 23 h

Procedure:
To a suspension of (±)-3-{[(3,5-difluorobenzyl)amino]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (47.0 mg, 0.106 mmol) in DCM (1.5 mL) was added 4-methylmorpholine (32.2 mg, 0.320 mmol). This mixture was sonicated to provided a finely powdered suspension. After cooling to 0° C., trimethylacetyl chloride (23.0 mg, 0.190 mmol) was added and the cooling bath was removed. After 23 hours, additional 4methylmorpholine (2 drops) and trimethylacetyl chloride (23.0 mg, 0.190 mmol) were added. After 7 hours, the reaction was quenched by the addition of one drop of methanol. This reaction mixture was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—100:1 to 94:6, to give the title compound as a white solid. MS: m/z=527 (M+1). HRMS: m/z=527.2253; calculated m/z=527.2253 for C31H29F2N4O2.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1)#[N:3].C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1)#[N:3]
Reactant: N#Cc1cc(F)cc(N2CCNCC2)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(F)cc(N2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In 30 ml of dichloromethane was suspended 2.54 g of 1-(3-cyano-5-fluorophenyl)piperazine hydrochloride, and the suspension was cooled to 0° C. To the suspension were added 7.3 ml of triethylamine and 3 ml of 2,2,2-trichloroethyl chloroformate, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform as a developing solvent. The fraction containing the desired compound was concentrated to give 4.79 g of the title compound.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1N.[C:9]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[F:22])[C@H:15]([OH:23])[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10]>>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[F:22])[C@H:15]([O:23][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=2)[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10]
Reactant: CC(=O)N1c2c(F)cccc2[C@H](O)C[C@@H]1C
Reactant: Nc1ccccc1F
Product: CC(=O)N1c2c(F)cccc2[C@H](Oc2ccccc2)C[C@@H]1C
Yield: 39 %

Procedure:
Cis-1-acetyl-8-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was obtained in the same manner as in Example 17, using 2-fluoroaniline. A compound was produced in the same manner as in Example 1, using 100 mg of cis-1-acetyl-8-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydro quinoline, and thus 52 mg (39%) of the title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[Si:21]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=[C:2]([Cl:1])[N:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(Cl)nc(CO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of 6-chloro-2-hydroxymethyl-4-methoxypyridine (1.85 g), which was prepared by a method mentioned in Tokkaihei 10-59942 (JP1998-59942A), and imidazole (0.87 g) in N,N-dimethylformamide (30 mL) was added tert-butyldimethylchlorosilane (1.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=85/15) to give 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (2.83 g). To a solution of N,N-diisopropylamine (0.54 mL) in tetrahydrofuran (20 mL) was added n-butyllithium (2.77 mol/L n-hexane solution, 1.25 mL) at −78° C., and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2-(tert-butyldimethylsilyloxy)methyl-6-chloro-4-methoxypyridine (1 g) in tetrahydrofuran (5 mL), and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added N,N-dimethylformamide (0.32 mL), and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine (0.28 g). The title compound was prepared in a similar manner to that described in Reference Example 15 using 6-(tert-butyldimethylsilyloxy)methyl-2-chloro-4-methoxy-3-formylpyridine instead of 2,6-dibromo-3-formylpyridine.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:20]([CH3:22])[CH3:21])[C:10]([C@H:12]1[C@H:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13]1=[O:19])=[O:11])=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:8][C@@H:9]([CH:20]([CH3:22])[CH3:21])[C:10]([C@H:12]1[C@H:16]([CH3:17])[C:15](=[O:18])[NH:14][C:13]1=[O:19])=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)[C@@H]1C(=O)NC(=O)[C@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)[C@@H]1C(=O)NC(=O)[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution cooled at 0° C. of 4.40 g (14.09 mmol) of (3R,4S)-3-[(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedione (preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643) in 20 ml of dioxane is admixed dropwise with 35 ml of 4N hydrochloric acid solution in 1,4-dioxane. When the addition has been made the mixture is warmed to room temperature and stirred for 2 h, before being concentrated in vacuo. The residue is treated with diethyl ether. The precipitated crystals are filtered off and dried under a high vacuum. Yield: 2.99 g of colorless crystals (86% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:3]=1
Reactant: Cc1nc(N)cc(N2CCc3ccccc32)n1
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(N)cc(-n2ccc3ccccc32)n1
Yield: 95.3 %

Procedure:
A mixture of 6-amino-4-(1-indolinyl)-2-methylpyrimidine (4.5 g, 20 mM), 30% w/w palladium on charcoal (0.45 g) and diphenyl ether (15 ml) was heated under reflux in an argon atmosphere for 1 hour. The solid was removed by filtration and the filtrate was diluted with hexane (100 ml) to give 6-amino-4-(1-indolyl)-2-methylpyrimidine (4.25 g, 95%) as a pale yellow solid, m.p. 176°-177° C.; microanalysis, found: C,69.5; H,5.5; N,24.4%; C13H12N4 requires C,69.64; H,5.36; N,25.0%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][CH2:10][CH2:11][N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:8].C(OCC)(=O)C>CCOCC>[NH2:8][CH2:7][CH2:9][CH2:10][CH2:11][N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(CCCC#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(CCCCN)c1ccccc1
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Lithium aluminium hydride (2 g) was added to dry ether (50 ml) in a stream of nitrogen, and a solution of N-(3-cyanopropyl)-N-methylaniline (9 g) in dry ether (10 ml) was added dropwise. The mixture was stirred for 1 hour and then heated under reflux for 2 hours. After decomposition of the excess reducing agent with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the desired compound (9.8 g) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[CH2:26][CH2:25][CH:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH:22]=2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[C:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH:22]=2)[CH3:10])[C:5]([C:35]#[N:36])=[C:4]([CH3:37])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2=CCC(NC(=O)OC(C)(C)C)CC2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2C2=CCC(N)CC2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round-bottom flask was charged with tert-butyl (4-(5-((S)-1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclohex-3-en-1-yl)carbamate (0.079 g, 0.157 mmol), DCM (2 mL), and TFA (0.969 mL, 12.57 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated using a stream of nitrogen. A portion of the crude material was purified via preparative HPLC (acid mode, 5-25% ACN/water gradient). The product-containing fractions were dried in vacuo to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (d, J=6.82 Hz, 3H), 0.97-1.16 (m, 1H), 1.30-1.51 (m, 2H), 1.57 (s, 3H), 1.63-1.94 (m, 3H), 2.66 (d, J=8.84 Hz, 1H), 3.07-3.15 (m, 3H), 4.69-4.88 (m, 1H), 5.02 (br s, 1H), 5.86 (d, J=3.03 Hz, 1H), 7.05 (d, J=3.03 Hz, 1H), 7.45 (d, J=4.04 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C22H26N8, 403. found 403.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].Cl[P:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=CC=CC=2)[CH:20]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O>[CH2:18]([P:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:19]1[CH:28]=[CH:27][CH:26]=[CH:21][CH:20]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2ccccc2c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: c1ccc(CP(c2ccccc2)c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
An electrolysis cell as described in Example 1 is used. The electrolyte comprises 70 ml of dimethylformamide (max. 0.1% of water), 0.4 g of anhydrous magnesium chloride and 6.62 g (0.030 mol) of chlorodiphenylphosphine. The electrolysis is carried out as described in Example 1. The electrolysis temperature is 25° C. After an amount of charge of 0.96 Ah, the electrolysis is ended. 4.64 g (0.025 mol) of benzyltrimethylammonium chloride are then introduced into the electrolyte with exclusion of air and the mixture is stirred at 35° C. After 3 h the reaction mixture contains, according to analysis by gas chromatography (internal standard: 2-methylnaphthalene), 5.72 g of benzyldiphenylphosphine (yield 83%, based on benzyltrimethylammonium chloride used) which can be isolated by workup as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[N:19](S(C(F)(F)F)(=O)=O)[N:18]=3)[N:8]=[C:9]2[O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:8]=[C:9]2[O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)c(F)cc3c(OC(C)C)n2)nn1S(=O)(=O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2cc3cc(N4CCOCC4)c(F)cc3c(OC(C)C)n2)n[nH]1
Temperature: 200 °C

Procedure:
Trifluoro-methanesulfonic acid 7-fluoro-1-isopropoxy-3-(5-methyl-1-trifluoromethanesulfonyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester (100 mg) and morpholine (100 ul) was added to NMP (1 ml). The mixture was heated at 200° C. for 1 hour under microwave irradiation. It was purified by preparative LC-MS to give (7-Fluoro-1-isopropoxy-6-morpholin-4-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (26 mg). LC-MS: m/e 386 (MH+).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: N#Cc1cccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1

Procedure:
0.248 g (0.446 mmol) of (2R*,4S*)-2-benzyl-1-(3-cyanobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.068 g (1.78 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR74## is obtained (0.157 g, 62% ) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.51, FD-MS: M+ =460.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.P(Br)(Br)[Br:26]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][Br:26]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 5, 2'-fluoro-5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is treated with phosphorus tribromide in chloroform to give 2'-fluoro-5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:31][C:32]([NH2:35])=[N:33][N:34]=1)[CH3:25]>>[CH2:24]([O:26][C:27]([CH2:28][S:29][C:30]1[S:31][C:32]([NH:35][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:3])=[N:33][N:34]=1)=[O:36])[CH3:25]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCOC(=O)CSc1nnc(N)s1
Product: CCOC(=O)CSc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)s1
Yield: 20.2 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl[(5-amino-1,3,4-thiadiazol-2-yl)thio]acetate (74.6 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(5-ethoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (16.4 mg).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH3:25]>CN(C)C=O>[CH2:23]([N:3]1[N:2]=[N:1][C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4]1)[CH2:24][CH3:25]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1nnc(-c2cnc3ccccn3c2=O)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A mixture of 0.4 g (0.00187 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, 15 ml of dimethylformamide, 0.25 g (0.00187 moles) of anhydrous potassium carbonate and 0.34 ml (0.00374 moles) of propyl bromide was stirred at 90° C. for 1 hour. The hot dark brown solution was filtered, and the filtrate was evaporated. The dark brown oily residue, which is the mixture of the title compounds, started to crystallize. To the oily crystals 10 ml of ethanol were added, and the crystals were collected. 0.15 g (31.3%) of 3-(2-propyl-2H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2 -a]pyrimidine was obtained, in the form of pale-yellow crystals, m.p.: 115°-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C1COCC1>[CH2:22]([O:21][CH:20]([O:24][CH2:25][CH3:26])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:23]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(COc1ccc(C(=O)OC)cc1)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture containing 10 g of methyl 4-hydroxybenzoate and 22.71 g of K2CO3 in 100 ml of THF is heated at 100° C. for 5 min and cooled to room temperature, 15.54 g of 2-bromo-1,1-diethoxyethane are added and the mixture is stirred for 2 hours at room temperature and then for 32 hours at 100° C., and is allowed to return to room temperature. The inorganic material is filtered off and then rinsed with DMF. The filtrate is evaporated and then taken up in DCM, washed with water (3 times) and then with saturated NaCl solution, dried over MgSO4 and evaporated. 16.68 g of the expected compound (greater than the theoretical mass) are obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3]1.[CH3:40]I>CN(C=O)C>[CH3:40][O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3]1
Reactant: CI
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate (6.9 g, 13.24 mMol) was dissolved in a mixture of MeI (12.4 mL, 198.6 mMol) and anhydrous DMF (15 mL) prior to the addition of Ag2O (6.1 g, 26.48 mMol) in one portion under an argon flush. The reaction was set to stir at rt in the dark. After stirring for 30 hr (the reaction was incomplete), it was diluted with CH2Cl2 and filtered through Celite. Filtered and concentrated to a yellow oil and flash chromatographed to get benzyl (1S,2R,4R)-4-methoxy-2-(trityloxymethyl)cyclohexylcarbamate (3.48 g) as a white foamy solid and recover the starting material.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:7]=1[C:8]1[CH:9]([C:27](=[O:29])[NH2:28])[CH2:10][CH2:11][CH2:12][C:13]=1[N:14]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:20]([N:14]1[C:13]2[CH2:12][CH2:11][CH2:10][CH:9]([C:27](=[O:29])[NH2:28])[C:8]=2[C:7]2[C:15]1=[C:16]([CH3:19])[CH:17]=[CH:18][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)c2c3c(n(Cc4ccccc4)c12)CCCC3C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A slurry of 64 mg (0.157 mmol) of [9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester in 2 ml of tetrahydrofuran and 7 ml of methanol was treated with 0.5 ml of an aqueous 2 N sodium hydroxide solution and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1 N HCl solution. After another extraction with ethyl acetate, the extracts were washed with brine, dried over magnesium sulfate and concentrated to afford a quantitative yield (62 mg) of the title compound. ESIMS m/e 393 (M++1), 391 (M+−1). NMR (300 MHz, d6-DMSO): δ12.98 (br, 1H); 7.30-7.18 (m, 3H); 6.82 (d+br, J=7.0, 3H); 6.73 (br, 1H); 6.59 (d, J=7.9,1H); 6.26 (d, J=7.9, 1H); 5.53 and 5.45 (ABq, J=18.1, 2H); 4.62 (s, 2H); 3.96 (br, 1H); 2.63 (m, 1H); 2.43 (m, 1H); 2.34 (s, 3H); 2.04 (m, 2H); 1.78 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.[OH-].[Na+].Cl.CO.[CH3:21][NH2:22]>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:22][CH3:21])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1cc(OC)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1.00 g portion of 4-chloro-2-methoxy-5-nitrobenzoic acid and 0.52 g of sodium hydroxide were dissolved in 20 ml of 40% methylamine methanol solution, followed by stirring at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured on crushed ice and adjusted to pH 4 with 6N hydrochloric acid aqueous solution. The thus precipitated product of interest was collected by filtration, washed with water and dried under a reduced pressure and then the resulting crude product was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 0.30 g of 2-methoxy-4-methylamino-5-nitrobenzoic acid.