Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[S:18]1[CH2:22][CH2:21][NH:20][C:19]1=[S:23]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:20]2[CH2:21][CH2:22][S:18][C:19]2=[S:23])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: S=C1NCCS1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSC1=S
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (3.1 g) and tetrahydrofuran (50 ml) were added 1,3-thiazolidine-2-thione (2.0 g) and triethyl amine (2.5 g). The mixture was stirred at 50° C. for 30 minutes under nitrogen atmosphere. The reaction mixture was filtered and the solvent was removed at a reduced pressure. To the residue was added water, and the solution is extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried with use of Glauber's salt. The solvent was distilled off and the resulting crystals were purified by silica gel column chromatography (developer: dichloromethane) and recrystallized from dichloromethane to obtain 3.3 g of the desired compound as yellow needle crystals (yield 82.5%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][O:28]1>>[C:34]([O:33][CH2:32][C@@H:30]1[CH2:29][O:28][C:27](=[O:26])[N:31]1[C:21]1[CH:22]=[CH:23][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[C:6]([CH3:25])=[CH:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:19][CH:20]=1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2)CC1
Yield: 91.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (2.08 g) described in Preparation Example 97 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.06 g), the title compound (2.29 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.70 g, 2.3 mmol) and 3-aminobenzyl alcohol (0.39 g, 3.2 mmol) in 1,4-dioxane (20.0 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.85 mmol). The mixture was heated at 100° C. for 16 h and the reaction was complete. To the mixture was added NaHCO3 (saturated aqueous solution) and the organic solvent was removed under vacuum, followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (0.90 g, 100%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:14])[CH3:13])[CH3:5].C(N(CC)CC)C.[F:22][CH:23]([F:33])[C:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]([CH3:32])[N:25]=1>ClCCl>[CH3:1][O:2][N:3]([CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:13])[CH3:14])[CH3:5])[C:29]([C:28]1[C:24]([CH:23]([F:33])[F:22])=[N:25][N:26]([CH3:32])[CH:27]=1)=[O:30]
Reactant: CONC(C)C1CCC(C)=CC1(C)C
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a stirred solution of O-methyl-N-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-hydroxylamine (diastereomer A), prepared as described in example P7, (88 mg; 0.45 mmol) and triethylamine (75 μl; 0.54 mmol) in dichloromethane (2 ml) was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (87 mg; 0.45 mmol). The reaction mixture was stirred at 24° C. for 16 h under nitrogen atmosphere. The mixture was concentrated to an oil which was subject to flash-master column chromatography (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 106 mg (66% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-amide as an amorph solid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[C:12]1(/[CH:18]=[CH:19]\[C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C\c1ccccc1
Agent: Cl
Product: O=C(/C=C\c1ccccc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride, and Z-3-phenylpropenoic acid; MS (ES+) 257 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C@@H:21]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:22]([NH:24][C@@H:25]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:26]([OH:34])[CH2:27][C@@H:28]([CH:31]([CH3:33])[CH3:32])[CH:29]=[CH2:30])=[O:23].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[CH:36]1([CH2:35][C@H:25]([NH:24][C:22]([C@@H:21]([NH:20][C:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH2:42][C:43]2[N:44]=[CH:45][NH:46][CH:47]=2)=[O:23])[C@@H:26]([OH:34])[CH2:27][C@@H:28]([CH:31]([CH3:33])[CH3:32])[CH:29]=[CH2:30])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
A mixture of 313 mg 1.18 mmol) of t-butoxycarbonyl-L-phenylalanine. 460 mg (1.18 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide, 0.15 ml (1.18 mmol) of 4-ethylmorpholine, 320 mg (2.36 mmol) of HOBT and 292 mg (1.42 mmol) of DCC in 20 ml of dimethylformamide was stirred at room temperature overnight. Thereafter, the separated precipitate was filtered off and the solvent was evaporated in a high vacuum. The residue was dissolved in ethyl acetate and then washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. After drying the organic solution over sodium sulfate, the solvent was evaporated under reduced pressure and, for purification, the residue (870 mg) was chromatographed on 30 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/ether yielded 410 mg of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate, melting point 161°.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I.I[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=CC=1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]4[CH:39]=[N:38][CH:37]=[CH:36][CH:35]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: ICc1cccnc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(OCc4cccnc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 3-(Iodomethyl)pyridine hydroiodide (381 mg, 1.1 mmol) was added in portions over a period of 3 hours. The heat source was removed and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 1400 mL and then 20% CMA in chloroform over 600 mL. The resulting solid was recrystallized from acetonitrile to provide 160 mg of 2-propyl-7-[(pyridin-3-yl)methoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 167.0-169.0° C. MS (APCI) m/z 351 (M+H)+; Anal. calcd for C19H18N4OS: C, 65.12; H, 5.18; N, 15.99. Found C, 65.25; H, 5.06; N, 16.03.
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])=[CH:10][CH:9]=1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:18]([O:17][CH:15]([O:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]\[CH2:5][OH:4])=[CH:13][CH:12]=1)[CH3:16])[CH3:19]
Reactant: CCOC(C)Oc1ccc(/C=C\COC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(C)Oc1ccc(/C=C\CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.8 Grams of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate and 50 ml of methanol solution containing 5 g of potassium carbonate were stirred at a room temperature for 2 hours. The solvent was removed by evaporation, and to the residue thus obtained was added water and extracted with ether. The ether extract was washed with water, dried and the solvent remove by evaporation to yield 4(Z)-(1-ethoxyethoxy)cinnamyl alcohol.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:32]#[N:33].[Na+].O>CS(C)=O>[C:32]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:33]
Reactant: [C-]#N
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
p-Toluensulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.0 g, 2.4 mmoles) was dissolved in dimethyl sulfoxide (10 ml), and sodium cyanide (0.3 g, 6 mmoles) was added, followed by stirring for 18 hours. To the reaction mixture was added water (100 ml) and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate-isopropyl ether (1:1) as the developing solvent to give (E)-1-cyano-7-phenyl-7-(3-pyridyl)-6-heptene (0.5 g, 76%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([N:10]=[C:11]=[S:12])[CH:7]=[CH:6][C:5]=1[F:13])=[C:2]=[S:3].[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(#N)C>[F:13][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:12])=[CH:9][C:4]=1[NH:1][C:2]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:3]
Reactant: CC(C)NC(C)C
Reactant: Fc1ccc(N=C=S)cc1N=C=S
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1ccc(F)c(NC(=S)N(C(C)C)C(C)C)c1)C(C)C

Procedure:
To a solution of 4.2 g. of 2,4-diisothiocyanatofluorobenzene in 100 ml. of acetonitrile is added 4.1 g. of diisopropylamine and the mixture is refluxed for 3 hours. The solvent is removed in vacuo and the residue is crystallized from acetonitrile to yield 5.1 g. of the title compound, melting point 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH:21]=O)[CH:6]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][NH:26][CH2:24][CH3:25])[CH:6]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Product: CCNCc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]#[N:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]#[N:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: N#Cc1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C#N)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.2 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile (5.04 g) and 3-(tertbutyloxycarbonylamino)pyrrolidine (3.96 g) were combined in acetonitrile (48 ml). The mixture was heated to reflux at which point all the solids dissolved. After refluxing for 15-20 minutes a precipitate formed. Stirring was continued at reflux overnight (22 hours). Triethylamine (6 ml) was then added and refluxing continued another seven hours before cooling to room temperature. The solid was collected by filtration and then washed with acetonitrile (15 ml) followed by a solution of triethylamine (5 ml) in acetonitrile (5 ml). The solid was dried under vacuum at 50° C. to give 7-[3-(tert-butyloxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile (7.65 g, 93%), mp 249°-250° C. (dec).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH:21]=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]([I:8])=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1nccc2cc3cccnc3n12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(=O)Nc1nccc2c(I)c3cccnc3n12
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
NIS (100 mg, 0.44 mmol) was portionwise added to a cooled (0° C.) solution of 9-Acetylaminopyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine (100 mg, 0.44 mmol) in CH2Cl2 (20 ml). The mixture was stirred for 15 min. The solution was diluted with CH2Cl2 (50 ml) and washed twice with water. The organic layer was dried and evaporated to obtain 20a (142 mg, 93%) as a bright yellow solid
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:16]=1.C(N(CC)CC)C>>[CH2:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:16]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1ccc(COC2CCNC2)cc1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(OCc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 70 %

Procedure:
A solution of 3-benzyloxypyrrolidine (182 mg, 1.03 mmol), 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (181 mg, 0.82 mmol) and triethylamine (387 mmol, 3.83 mmol) was refluxed for 3 hours. After removal of the solvent, the residue was purified by silica gel column chromatography (eluent; dichloromethane/ethanol=10/1) and washed with ethyl acetate to afford 2-(3-benzyloxy-pyrrolidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (208 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[C:53]([C:56]1[N:57]=[N:58][NH:59][CH:60]=1)(O)=[O:54]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:53]([C:56]2[N:57]=[N:58][NH:59][CH:60]=2)=[O:54])[CH2:25]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2c[nH]nn2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 72 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 4-carboxy-1,2,3-triazole as the starting materials in 72% yield. LCMS for C25H24ClN10O2 (M+H)+: m/z=531.0.
Reaction SMILES: [NH2:1][C:2]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)([CH3:15])[CH2:3][NH:4][C:5]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CC(O)=O.C([O-])(O)=O.[Na+]>>[F:23][C:18]1[CH:17]=[C:16]([C@@:2]2([CH3:15])[NH:1][C:11](=[O:12])[C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[NH:4][CH2:3]2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: COC(=O)C1(NCC(C)(N)c2cc(F)cc(F)c2)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCCC2)C(=O)N1

Procedure:
A solution of methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexane carboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, then poured into saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH—100:0 to 92:8, to give the racemic product. The enantiomers were separated by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—40:60:0.1. The first major peak to elute was (3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one, the title compound, and the second major peak to elute was (3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one. MS: m/z=295 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)CCCN2
Temperature: 20 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of #214 (750 mg, 2.25 mmol, 1 eq.) in dichloromethane (20 mL) was added dropwise trifluoracetic acid (2 mL) at 0° C. and then the solution was stirred at 20° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (20 mL). The solution was basified with sodium carbonate and extracted with ethyl acetate/tetrahydrofuran (30 mL×3). The organic phase was dried over sodium sulfate and concentrated in vacuo to afford #215 (450 mg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.70 (d, 2H), 6.40 (m, 1H), 3.73 (s, 3H), 3.67 (m, 1H), 3.30 (m, 2H), 2.96 (m, 1H), 2.75 (m, 3H), 1.96 (m, 2H), 1.50 (br, 2H), 1.26 (br, 1H), HPLC (Protocol Y): m/z 235.14 [M+H+] retention time=4.35 minutes (purity >96%). Chiral HPLC retention time: 5.71 min (purity=98%). (Column: Chiralcel OJ-H, 150×4.6 mm, 5 μm; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% over 15 minutes; Flow rate: 2.5 mL/minute.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[C-:31]#[N:32].[Na+]>CN(C)C=O>[C:27]([O:26][C:24]([N:5]1[CH2:6][CH2:7][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:9][CH:4]1[CH2:3][CH2:2][C:31]#[N:32])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved 2-(2-bromoethyl)-1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen -2-yl)sulfonyl]piperazine (980 mg), followed by the addition of sodium cyanide (102 mg). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the resulting mixture was washed with water and saturated aqueous NaCl solution, each once. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (842 mg) was obtained as a colorless foam.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34](O)=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH2:33][C:34]([NH:18][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH:16]=[CH2:17])=[O:35])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:20]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: C=CCCC(N)c1ccccc1N1CCCCC1
Product: C=CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-4-penten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.