Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH2:15])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18].[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:45])[CH2:31][CH2:30]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:15][C:17]([N:29]1[CH2:30][CH2:31][CH:32]([N:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:45])[CH2:33][CH2:34]1)=[O:18])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][N:13]=[CH:14][C:8]=2[CH2:7]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)C(N)CN1CCc2[nH]ncc2C1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COC(=O)C(CN1CCc2[nH]ncc2C1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 2-amino-3-(1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-propionic acid methyl ester (260 mg, 1 equiv) in methylene chloride (2 mL, 0° C.) was added carbonyl diimidazole (188 mg, 1 equiv). After 15 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (295 mg, 1.1 equiv) was added in one portion. The ice bath was removed and stirring continued overnight. The reaction was concentrated and purified by column chromatography to give 118 mg (21%). 1H-NMR (CDCl3, 500 MHz) δ 1.60–1.80 (m, 4H), 2.70–3.05 (m, 8H), 3.45 (s, 2H), 3.56 (d, J=13.4, 1H), 3.62 (d, J=13.4, 1H), 3.75 (s, 3H), 4.02 (d, J=13.1, 1H), 4.10 (d, J=12.5, 1H), 4.24 (s, 2H), 4.45–4.57 (m, 2H), 5.79 (bs, 1H), 6.68 (d, J=7.94, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 7.00 (d, J=7.3, 1H), 7.13 (dd, J=7.6, 7.3, 1H), 7.25 (s, 1H), 7.82 (s, 1H). Mass spec.: 482.27 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14]C(OC(C)(C)C)=O)([CH3:13])[CH3:12])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CC(C)(C)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(C)(C)N)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 3-(2-tert-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester (Preparation 20) (1.6 g, 5.2 mmol) in dichloromethane (160 mL) at 0° C. was treated with trifluoroacetic acid (13.6 mL) and left to warm to room temperature over 2 hours. The solvent was removed in vacuo and the product purified by cation exchange chromatography (methanol followed by 2M ammonia in methanol) to yield the title compound as an amber oil (1.06 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(O)=C(C(CS(C2C=CC=CC=2OC)(=O)=O)=CC=1)[C:32](OC)=[O:33].O1C=CC(B(O)O)=C1>>[O:25]1[CH:26]=[CH:27][C:23]([C:14]2[C:15]([OH:22])=[C:16]([C:11]([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[O:33][CH3:32])(=[O:8])=[O:9])=[CH:12][CH:13]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(Br)c1O
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-hydroxy-6-(2-methoxybenzenesulphonylmethyl)benzoate (Intermediate 67) and furan-3-yl boronic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[NH:15]1[CH2:20][CH:19]=[C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.O>CS(C)=O.[OH-].[Na+]>[NH:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][O:4][C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[CH2:16][CH:17]=2)=[CH:22]1
Reactant: C1=C(c2c[nH]c3ncccc23)CCNC1
Reactant: ClCCOc1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ncccc23)CCN(CCOc2cccc3ncccc23)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 5-(2-chloroethoxy)quinoline (0.5 g, 24 mmol), ), 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.58 g, 29 mmol) and triethylamine (0.67 ml, 48 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 4 hours at 80° C. The mixture was poured into water dilute with sodium hydroxide solution and extracted with ethyl acetate (3×100 ml). The organic layer was washed with water (3×100 ml), sodium bicarbonate and dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum to give a pale yellow solid, which was triturated with ethanol-ethyl ether to afford a pale yellow solid: mp 202-205° C.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38]>N.CO>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)cc1Cl)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.6 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.05 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2,4-Dichlorobenzenesulfonyl chloride (25 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.9 mg). MS m/z 398 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:19][CH2:18][CH2:17][CH:16]4[C:11]3([CH2:12][CH2:13][N:14](C)[CH2:15]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.N#CBr.[OH-].[K+]>C(Cl)Cl.C(O)CO>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH2:19][CH2:18][CH2:17][CH:16]4[C:11]3([CH2:12][CH2:13][NH:14][CH2:15]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC1CCCC3CN(C)CCC231
Agent: N#CBr
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: ClCCl
Product: COc1cccc2c1OC1CCCC3CNCCC231

Procedure:
Thus, 9-methoxy-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (Example 2d) is heated to reflux with cyanogen bromide in methylene chloride and the crude product is then heated with potassium hydroxide in ethylene glycol to 170° to give 9-methoxy-2,3,4,4a,5,6,7,7a-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (R1 =H; R2 =OMe; R3, R4, R5 =H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Reactant: Cc1ccc(Cl)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)OC)cnc12
Yield: 100.3 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.2 g, 7.13 mmol) obtained in Example 21, step 2 and 2-chloro-5-methylaniline (1.64 g, 11.6 mmol), the title compound (2.78 g, 92%) was obtained.
Reaction SMILES: [Br-].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][CH:35]=1)=O>>[O:2]([CH2:9][CH2:10][CH2:11][CH:12]=[CH:32][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:38][CH:39]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(C=O)cc1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CCOC(=O)CCc1ccc(C=CCCCOc2ccccc2)cc1

Procedure:
Preparation takes place in analogy to Example XLIII from (4-phenoxybutyl)-(triphenyl)phosphonium bromide and ethyl 3-(4-formylphenyl)propanoate. The product is obtained as an E/Z mixture.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH:21][S:25]([CH:22]4[CH2:24][CH2:23]4)(=[O:27])=[O:26])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2)C1CC1

Procedure:
The title compound, MS (ISP) m/e=384.1 [(M+H)+], was prepared from (R)—N2-indan-1-yl-4H-benzo[d][1,3]oxazine-2,5-diamine (example 2) and cyclopropylsulfonyl chloride according to the procedure described for example 5.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[CH2:19]([N:26]1[CH2:30][CH2:29][N:28]([C:31]2[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=2)[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:30][CH2:29][N:28]([C:31]2[S:32][C:33]([C:37]([NH:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[F:10])=[O:38])=[C:34]([CH3:36])[N:35]=2)[C:27]1=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccc1F
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1F
Yield: 44 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2-fluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 44% yield: mp 167-168° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.20 (m, 7H), 7.11-7.00 (m, 2H), 6.03 (s, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.45 (s, 2H), 4.07-4.00 (m, 2H), 3.46-3.40 (m, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 159.4 157.4, 155.4, 153.0, 135.5, 130.3, 129.4, 129.3, 128.9, 125.4, 124.4, 117.2, 115.5, 115.8, 47.9, 42.0, 41.6, 38.7, 17.1; MS (ES+) m/z 425.2 (M+1).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC(CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CC(CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 3 h

Procedure:
To a solution of the more polar stereoisomer of (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide (90 mg) in ethanol/tetrahydrofuran (350 mL; 2:1) was added 10% palladium on charcoal (30 mg). The material was stirred with a constant stream of hydrogen gas bubbling through it. After 3 hours TLC (10% CH3OH/CH2Cl2) showed the reaction was complete. The material was filtered through a bed of celite (3X) and concentrated under reduced pressure to an almost dry residue. Methylene chloride (15 mL) was added and the material was again concentrated under reduced pressure until almost dried and then repeated. To the residue was added 3-4 drops of methanol followed by methylene chloride (15 mL). The material was stirred with cooling (ice bath) and ether (5 mL) and then hexane (2 mL) was added. A crystalline material slowly emerged and was collected by filtration to yield 50 mg of the more polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide, m.p. 197-201° C., [α]D23 =-85.1° (3.5 mg/1.0 mL DMSO).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
A suspension of 1.85 g (4.74 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of N,N-dimethylformamide was treated with 2.40 g (23.7 mmol) of dipropylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. There were obtained 2.03 g (94%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a pale yellow oil; [α]D20 =+29.3° (MeOH, c=1%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[C:29]([O:35][CH3:36])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32].Cl>CS(C)=O>[C:31]([CH:30]([C:29]([O:35][CH3:36])=[O:34])[C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])(=[O:32])[CH3:33]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(C(C)=O)C(=O)OC)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 51.6 %

Procedure:
To a solution of diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (1.0 g, 3.03 mmol.) in dimethyl sulfoxide (DMSO, 3mL) were added potassium carbonate (1.25 g, 9.09 mmol.) and methyl acetoacetate (0.99 mL, 9.0 mmol.). The resulting mixture was stirred at 70° C. for 6 hours. The reaction mixture was cooled to room temperature, neutralized with diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The dried portion was concentrated to leave a residue. The residue was purified by silica gel column chromatography (Wako Gel C-330, available from Wako Jyunyaku Industry Co., Ltd., toluene/ethyl acetate=100/4, v/v), to give 0.64 g (yield: 52%) of the desired compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]=O)=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].[CH3:29][NH:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:30]([CH3:31])[CH3:29])=[C:19]([CH:22]([O:23][CH3:24])[O:25][CH3:26])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CNC
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(C)C)CCCN2C(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 36, 25 mg, 0.066 mmol) and dimethylamine (7.9 M in water, 0.017 ml, 0.131 mmol) in DCM (0.5 ml) was added sodium triacetoxyborohydride (27.8 mg, 0.131 mmol). The reaction mixture was stirred at room temperature for 1 h, poured into sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by supercritical fluid chromatography (SFC 1, NH2 column) to give the title compound as a colorless solid. (UPLC-MS 3) tR 0.73 min; ESI-MS 411.2 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:22][C@@H:21]3[C@@:16]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([N:17]=[C:18]([NH:23]C(=O)C4C=CC=CC=4)[S:19][CH2:20]3)[CH2:15]2)=[N:12][CH:13]=1.Cl.CON>C(O)C>[F:7][C:8]1[CH:13]=[N:12][C:11]([N:14]2[CH2:22][C@@H:21]3[C@@:16]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([N:17]=[C:18]([NH2:23])[S:19][CH2:20]3)[CH2:15]2)=[N:10][CH:9]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Pyridine (20 mL, 197 mmol) is added to a mixture of N-[(4aR,7aS)-6-(5-fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (9.5 g, 22 mmol), O-methylhydroxylamine hydrochloride (15 g, 175 mmol) in ethanol (85 mL) and the mixture is stirred at 60° C. for 2 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water (100 mL) and ethyl acetate (100 mL) and the pH to 2 using 1 M hydrochloric acid. The aqueous layer is separated and the pH is adjusted to 10 using 2 M sodium hydroxide. The resulting aqueous solution is extracted with ethyl acetate (2×100 mL). The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a 5% solution of dichloromethane/2 M ammonia in methanol. Chiral Analysis of the product; column: Chiralpak AD 0.46×15 cm, 5 μm; eluent: 100% (methanol with 0.2% dimethylethylamine); flow: 0.75 ml/min at UV 254 nm; Rt=6.9 minutes. (4.6 g, 64%, >98% ee). ES/MS (m/e): 330 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:26]([CH3:27])[CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNC1CCN(C)CC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-methyl-4-(methylamino)piperidine using procedure C yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[N:16][C:17](Cl)=[CH:18][C:13]=3[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)/C=C\C(O)=O.ClC1[N:38]=[N:37]C2CCNCC=2C=1.C(C1C=CC=CC=1C(Cl)=O)(C)(C)C>C(O)C>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[N:16][C:17]([NH:37][NH2:38])=[CH:18][C:13]=3[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: CC(C)(C)c1ccccc1C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
The 6-(p-tert.-butylbenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 34.2 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 25 g of tert.butylbenzoyl chloride. M.P. 157°-160° (decomp., from 95% ethanol).
Reaction SMILES: ClC1(Cl)[C@@H]2[C@@H](CCC=C2)C1=O.[CH3:12][O:13][C@@:14]12[C:21](=[O:22])[CH2:20][C@@H:19]1[CH:18]=[CH:17][CH2:16][CH2:15]2>>[CH3:12][O:13][C@:14]12[C:21](=[O:22])[CH2:20][C@H:19]1[CH:18]=[CH:17][CH2:16][CH2:15]2
Reactant: CO[C@]12CCC=C[C@H]1CC2=O
Agent: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Product: CO[C@@]12CCC=C[C@@H]1CC2=O

Procedure:
Similarly, starting with (1S,6R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one in place of the racemic compound in Preparation 3.A. above, (1S,6S)-6-methoxybicyclo[4.2.0]oct-2-en-7-one is prepared. Similarly, starting with the (1R,6S)-compound, (1R,6R)-6-methoxybicyclo[4.2.0]oct-2-en-7-one is prepared.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]1[CH2:21][C@@H:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][N:18]1[C:30](OC(C)(C)C)=[O:31])[CH2:9][CH2:10]C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C[C@@H]1C[C@@H](OCC2C=CC=CC=2)CN1C(OC(C)(C)C)=O)CCC(OCC)=O)C1C=CC=CC=1.Cl.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:30](=[O:31])[N:18]2[CH2:19][C@H:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][C@@H:17]2[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)C[C@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)CCN(Cc1ccccc1)C[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1CCN(Cc2ccccc2)C[C@H]2C[C@@H](OCc3ccccc3)CN12
Temperature: 22.5 °C
Reaction time: 22 h
Yield: 35 %

Procedure:
To a 2:3 mixture of tert-butyl (2R,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate and tert-butyl (2S,4R)-2-{[benzyl(3-ethoxy-3-oxopropyl)amino]methyl}-4-(benzyloxy)pyrrolidine-1-carboxylate (25 g, 0.050 mol, Part B) in methanol (125 mL) was added a solution of 4.0 M HCl/dioxane (125 mL) while maintaining the internal temperature below 5° C. The reaction mixture was allowed to stir at 20-25° C. for 22 hours and was then concentrated. The residue was stirred with toluene (250 mL) and 1 M sodium carbonate solution (250 mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The toluene filtrate was heated to reflux at 115° C. for four hours and was then concentrated. The isomers were separated by silica gel column chromatography eluted with ethyl acetate/hexane (60:40) to give (8R,9aR)-2-benzyl-8-(benzyloxy)octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (6.2 g, 35%) as dark brown oil. HPLC (column: Agilent ZORBAX® RX-C8, 150 mm×4.6 mm, 5 μm; gradient: 10-80% acetonitrile in 0.1% phosphoric acid/water over 13 minutes with a hold at 80% for an additional five minutes; flow rate: 1.0 mL/minute; temperature: 30° C.). Retention time for the titled isomer was 7.147 minutes and for the (8R,9aS) isomer, 6.704 minutes. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.23 (m, 10 H), 4.62-4.47 (m, 2 H), 4.11-3.96 (m, 2 H), 3.83-3.75 (m, 1 H), 3.64-3.56 (m, 3 H), 3.02-2.74 (m, 3 H), 2.61-2.53 (m, 1 H), 2.47-2.36 (m, 3 H), 1.88-1.79 (m, 1 H).