Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mL×2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give colorless oil (3.01 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24](=[O:29])[NH:25][CH2:26][C:27]=2[N:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:37])[N:7]([C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24](=[O:29])[N:25]([CH3:41])[CH2:26][C:27]=2[N:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CNC(=O)N3c2ccc(Cl)cc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C)C(=O)N3c2ccc(Cl)cc2)c(OC)c1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of [1-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 21, low RF compound from Step 1) (120 mg, 0.23 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 14 mg, 0.34 mmol, 1.5 equiv) and the reaction mixture was stirred for 1 h. Iodomethane (30 μL, 0.46 mmol, 2 equiv) was added and stirring was continued overnight. Water was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-100%) to afford [1-(4-chloro-phenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl]-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (49 mg). MS: [M+H]+=539.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:42]=[CH:41][CH:40]=[C:39]([C@H:43]([OH:54])[C@@H:44]3[N:49]4[CH2:50][C@H:51]([CH:52]=[CH2:53])[CH:46]([CH2:47][CH2:48]4)[CH2:45]3)[C:37]=2[CH:38]=1.CO.ClCCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:42]=[CH:41][CH:40]=[C:39]([C@H:43]([OH:54])[C@@H:44]3[N:49]4[CH2:50][C@H:51]([CH:52]=[CH2:53])[CH:46]([CH2:47][CH2:48]4)[CH2:45]3)[C:37]=2[CH:38]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-Val-OH (2.00 g.,9.26 mmol) and DCC (1.90 g, 9.26 mmol) were dissolved in dry DMF (20 ml) under a nitrogen atmosphere. The mixture was stirred continuously for one hour at 0° C. A solution of quinidine (1.50 g, 4.63 mmol) and DMAP (0.06 g, -0.65 mmol) in DMF (100 ml) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred and allowed to warm to room temperature. After 24 hours, the reaction was checked by TLC (1:13 methanol/dichloromethane mixture) and LC-MS analysis, and was found to be complete. The urea derivative was removed by filtration and washed with ethyl acetate. Solvents from the combined filtrate and washing were totally removed under reduced pressure.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][CH:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:14]1([O:13][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][C:4]4[CH:3]=[CH:2][N:21]([CH2:22][CH:23]([OH:25])[CH3:24])[C:5]=43)=[CH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(OC3CCCC3)ccc1C2
Reaction time: 0.75 h
Yield: 48.5 %

Procedure:
A solution of 2.58 g of (RS)-2-(2-oxoethyl)-6-cyclopentoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.44 g (48%) of (RS)-1-(7-cyclopentoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH:16]([CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([NH:15][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=1)[CH2:24][CH3:25])[CH:21]([CH3:22])[CH3:23]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: CCC(NC(=O)Cc1cccc(C(F)(F)F)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 3-trifluoromethyl-phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:12][C:13]([C:16]1[C:21]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:19]=[C:18]([CH:33]=[N:34]O)[N:17]=1)([CH3:15])[CH3:14].N1C=CC=NC=1>C(#N)C>[CH3:15][C:13]([C:16]1[C:21]([O:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:19]=[C:18]([C:33]#[N:34])[N:17]=1)([CH3:12])[CH3:14]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=NO)nc1C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1cncnc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COCCOCOc1c(C(C)(C)C)nc(C#N)nc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.3 %

Procedure:
Dimethylformamide (0.05 g, 0.6 mmoles) is cooled to 0° C. in 10 mL of acetonitrile under argon. Oxalyl chloride (0.1 g, 0.9 mmoles) is added and the reaction mixture is stirred at 0° C. for 10 minutes. 4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidinecarboxaldehyde oxime (0.2 g, 0.6 mmoles) is dissolved in 10 mL of acetonitrile and cooled to 0° C. The vilsmier reagent prepared above is added to the pyrimidine solution at 0° C. After 3 hours at 0° C, the reaction is quenched by the addition of 10 mL of saturated sodium bicarbonate and extracted with ether (3×10 mL). The organic extract is washed with 50 mL of brine and dried over magnesium sulfate. Evaporation of the solvent gives a red oil which is purified by flash chromatography (silica, 10% ether/chloroform) to give 4,6-bis (1,1-dimethylethyl) -5-[(2-methoxyethoxy)methoxy]-2-pyrimidinecarbonitrile (43 mg, 22%) as an oil.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([OH:7])=O)([CH3:4])[CH3:3].[CH3:15][NH:16][O:17][CH3:18].Cl.CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[NH:1][C:2]([C:5](=[O:7])[N:16]([O:17][CH3:18])[CH3:15])([CH3:3])[CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 80 %

Procedure:
To a stirred mixture of Boc-Aib-OH (5 g, 24.61 mmol, 1 eq), MeNHOMe.HCl (2.88 g, 29.53 mmol, 1.2 eq), DMAP (3.61 g, 29.53 mmol, 1.2 eq), i-Pr2NEt (5.02 mL, 29.53 mmol, 1.2 eq) and CH2Cl2 (100 mL) was added DCC (6.09 g, 29.53 mmol, 1.2 eq). The mixture was stirred at room temperature for 5 days. The mixture was filtered to remove precipitated N,N′-dicyclohexylurea and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with 10% aqueous citric acid (3×200 mL), 10% aqueous NaHCO3 (3×200 mL) and saturated aqueous sodium chloride (3×200 mL), and dried over MgSO4. Removal of the solvent yeided the crude product which was purified by column chromatography (hexane/ethyl acetate 60:40) to afford [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (4.85 g, 80%) as a white solid. 1H NMR (200 MHz, CDCl3) δ(ppm): 1.43 (s, 6H), 1.58 (s, 9H), 3.22 (s, 3H), 3.69 (s, 3H), 6.95 (bs, 1H). MS (ESI, +ve ion): m/z 247.2 (M+1)+.
Reaction SMILES: Br[C:2]1[N:3](C2CCCCO2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.C[O-].[Na+].[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28].[CH3:34][O:35]C1CCCC1>CC1CCCO1.CO>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH3:17][C@H:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:35][CH3:34])[NH:3]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: COC1CCCC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Bromo-2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.26 kg, corrected for residual solvent) was dissolved in anhydrous methyl tetrahydrofuran (MeTHF) (11.4 L) and 25% sodium methoxide in methanol (2.65 L, 3.5 eq) was added. The resultant reaction mixture was heated to 65+/−5° C. for 3 hrs. The complete reaction was cooled to room temperature and washed with 20% w/v aqueous ammonium chloride solution (2×6.3 L) and brine (6.3 L). The organic phase was dried with MgSO4 (1.8 kg) and filtered, washing through with MeTHF (6.3 L). The combined organic phases were evaporated to 6.3 L by vacuum distillation. MeOH (2.5 L) and TFA (1.26 L, 5 eq) were added and the mixture heated to 60° C. for 1.5 hours. Cyclopentyl methyl ether (CPME) (6.3 L) was added and the mixture reduced to 6.3 L by vacuum distillation. CPME (6.3 L) was again added and the reaction further concentrated to 6.3 L, when solids precipitated. The slurry was cooled to 10° C. then aged for 30 min. The product was filtered and washed with TBME (2×3.8 L) and dried in vacuo at 40° C. to afford a white solid (886 g, 74% theoretical yield).
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1)([O-])=O>[Ni].C(O)C.C1COCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:9]2[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[CH:15]=[C:7]([NH2:4])[CH:8]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])cc3ccoc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
Raney nickel (slurry in ethanol) and hydrazine hydrate (66 μL, 1.36 mmol) were added to tert-butyl 4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (123 mg, 0.34 mmol; obtained in Step 1) in ethanol:THF (4:1; 10 mL). The mixture was stirred at room temperature for 1 h. Unreacted starting material was still present and additional Raney nickel and hydrazine hydrate (33 μL, 0.68 mmol) were added with continuos stirring for 1 h. The mixture was filtered through a pad of Celite, which was rinsed several times with ethanol. Evaporation of the solvent gave 119 mg (quantitative) of the title amine as a green sticky oil which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[N:3]=[CH:4][C:5]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[NH2:15]
Reactant: Clc1ncc2c(n1)CCCCCC2
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncc2c(n1)CCCCCC2

Procedure:
2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine (1.5 g) was treated with anhydrous pyridine (15 mL) and anhydrous hydrazine (7 mL) at 120° C. for 3.75 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine as a beige solid, 1.28 g; 1H NMR (CDCl3, 300 MHz) 8.00 (s, 1H), 6.63 (br s, 1H), 3.93 (br s, 2H), 2.76 (m, 2H), 2.60 (m, 2H), 1.74 (m, 2H), 1.63 (m, 2H), 1.40 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 170.57, 163.81, 157.22, 124.14, 34.31, 32.65, 30.24, 28.66, 26.32, 26.08; MS (ES) 193 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](=O)[O:33][C:32]1=O.COC(OC)OC.O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C1COCC1>[CH3:30][C:3]1[C:2]([N:1]2[C:34](=[O:33])[C:35]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:31]=[CH:32]2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=[N+]([O-])[O-]
Agent: [La+3]
Solvent: COC(OC)OC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A burgundy solution of 4-(3-amino-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxamide (0.0612 g, 0.140 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.057 g, 0.351 mmol), trimethoxymethane (0.154 ml, 1.402 mmol) and lanthanum nitrate hexahydrate (0.018 g, 0.042 mmol) in THF (0.334 mL) in a sealed vial was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DMSO (0.2 mL) and MeOH (1.6 mL), and subjected to autoprep reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combine extract was dried over Na2SO4 and concentrated in vacuo to give the desired product (0.0135 g, 0.024 mmol, 17.1% yield) as a tan solid. LC/MS (M+H)=531.29; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for major atropoisomer) δ ppm 11.48 (1 H, s), 8.42 (1 H, s), 8.21-8.28 (2 H, m), 8.15 (1 H, s), 7.88-7.94 (1 H, m), 7.76-7.81 (1 H, m), 7.69-7.74 (1 H, m), 7.53-7.69 (4 H, m), 7.27 (1 H, d, J=2.22 Hz), 6.79-6.86 (1 H, m), 3.74-3.81 (4 H, m), 3.16-3.23 (4 H, m), 1.81 (3 H, s).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[CH3:20][NH:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:20][N:21]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4])[CH3:22]
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 6 ml of 40% strength aqueous dimethylamine solution and 10 ml of methylene chloride are stirred at 35° C. for 2 hours; 0.35 g of sodium carbonate is added, and the mixture is concentrated to dryness in vacuo. A little water is added; the solution is extracted repeatedly by shaking it with chloroform, and the organic solution is dried with sodium sulfate and concentrated to dryness. 1.9 g of 4-(dimethylaminoacetyl)-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one are thus obtained. 4-(Diethylaminoacetyl)-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one [m. 196°-197° C. (from toluene)] is obtained analogously by reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one with a corresponding amount of diethylamine (instead of dimethylamine).
Reaction SMILES: Cl.Cl.Cl.Cl.C(NN=C(NCCCC(C)CNC(=NNC(=N)N)[NH:40][C:41]1[CH:46]=[C:45]([C:47](=[O:49])[CH3:48])[CH:44]=[C:43]([C:50](=[O:52])[CH3:51])[CH:42]=1)NC1C=C(C(=NNC(=N)N)C)C=C(C(=NNC(=N)N)C)C=1)(=N)N.[C:59]([C:62]1[CH:63]=[C:64]([CH:66]=[C:67]([C:69](=[O:71])[CH3:70])[CH:68]=1)[NH2:65])(=[O:61])[CH3:60].[CH3:72][CH:73]([CH2:78][CH2:79][CH2:80][N:81]=[C:82]=[O:83])[CH2:74][N:75]=[C:76]=[O:77].COC(C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:59]([C:62]1[CH:63]=[C:64]([NH:65][C:76]([NH:75][CH2:74][CH:73]([CH3:72])[CH2:78][CH2:79][CH2:80][NH:81][C:82]([NH:40][C:41]2[CH:42]=[C:43]([C:50](=[O:52])[CH3:51])[CH:44]=[C:45]([C:47](=[O:49])[CH3:48])[CH:46]=2)=[O:83])=[O:77])[CH:66]=[C:67]([C:69](=[O:71])[CH3:70])[CH:68]=1)(=[O:61])[CH3:60]
Reactant: CC(=O)c1cc(NC(=NNC(=N)N)NCC(C)CCCNC(=NNC(=N)N)Nc2cc(C(C)=NNC(=N)N)cc(C(C)=NNC(=N)N)c2)cc(C(C)=O)c1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Reactant: CC(CCCN=C=O)CN=C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(=O)c1cc(NC(=O)NCCCC(C)CNC(=O)Nc2cc(C(C)=O)cc(C(C)=O)c2)cc(C(C)=O)c1

Procedure:
Compound 42, FIG. 7J.42: A suspension of 3,5-diacetylaniline (0.354 g) in methylene chloride (7 mL) containing 4-dimethylaminopyridine (5 mg) was treated with 2-methyl-1,5-pentanediyl diisocyanate (0.18 mL). After heating at reflux for 2 hr, the mixture was cooled. An aliquot was treated with t-butyl methyl ether to give seed crystals which were added to the reaction mixture. After stirring several hr, filtration gave 0.120 g of 1,5-bis[([(3,5-diacetylphenyl)-amino]carbonyl)amino]-2-methylpentane, mp 128° C. This tetraketone (0.100 g), aminoguanidine hydrochloride (0.115 g), and aminoguanidine dihydrochloride (3 mg) were heated in 95% ethanol (2.5 mL) for 18 hr. Cooling and filtration gave 0.16 g of 1,5-bis[([(3,5-diacetylphenyl)amino]carbonyl)amino]-2-methylpentane tetrakis(amidinohydrazone) tetrahydrochloride (Compound 42) as the tetrahydrate, mp 258-9° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1>CN(C)C(=O)C.O1CCCC1>[F:46][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]3[N:24]([CH:47]=[C:21]([NH:20][C:5]([CH:3]4[CH2:4][CH:2]4[CH3:1])=[O:7])[N:22]=3)[N:25]=2)=[CH:35][C:34]=1[NH:36][C:37]([C:39]1[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=1)=[O:38]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CC1CC1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2F)n(C)n1
Yield: 24.7 %

Procedure:
Using 2-methylcyclopropanecarboxylic acid (72 mg, 0.72 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (63 μL, 0.72 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 239, the title compound (55 mg, 25%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[NH:21]1[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:22]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1
Yield: 33.3 %

Procedure:
Prepared according to general procedure 21. A solution of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (2.0 g, 6.3 mmol), tert-butyl azetidin-3-ylcarbamate acetate (1.61 g, 6.9 mmol) sodium tert-butoxide (2.55 g, 26.5 mmol), biphenyl-2-yl-di-tert-butylphosphine (224 mg, 0.76 mmol), and Pd2(dba)3 (172 mg, 0.19 mmol) in toluene (16 mL) was stirred at 75° C. for 16 h. The reaction mixture was poured into H2O, and the pH was adjusted to 6. The aqueous layer was extracted 4 times with CH2Cl2, and the organics were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 50-70% EtOAc in hexanes gave tert-butyl 1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-ylcarbamate (0.86 g, 33%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=411.0; tR=2.54 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=3[N:7]1[C:6]2=[O:22])[CH3:2].[CH3:23]Br>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[N:13]([CH3:23])[C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=3[N:7]1[C:6]2=[O:22])[CH3:2]
Reactant: CCc1ccc2nc3[nH]c4cc(C)c(C)cc4n3c(=O)c2c1
Reactant: CBr
Product: CCc1ccc2nc3n(C)c4cc(C)c(C)cc4n3c(=O)c2c1

Procedure:
2-Ethyl-6,8,9-Trimethylbenzimidazo[2,1-b]quinazoline-12(6H)one is prepared with 2-ethyl-8,9-dimethylbenzimidazo[2,1-b]-quinazolin-12(6H)one and methyl bromide.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH:6](Cl)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][SH:30])=[CH:24][CH:23]=1.COC(=O)C(SCCC1C=CC(F)=CC=1)CC1C=CC(C(C)(C)O[SiH2]C(C)(C)C)=CC=1>>[Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5](=[O:18])[CH:6]([S:30][CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1
Reactant: Fc1ccc(CCS)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cl)Cc1ccc(CCO)cc1
Agent: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCO)cc1)SCCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-chloro-3-[4-(2-hydroxy-ethyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (2.57 g, 7.14 mmol) and 2-(4-fluoro-phenyl)-ethanethiol (1.23 g, 7.85 mmol) as described for 3-[4-(tert-butyl-dimethyl-silanyloxy-methyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester. After purification by flash chromatography with n-heptane/EtOAc 5:1 as the eluent the product was obtained as an oil (1.0 g, 29.2%). 1H NMR (300 MHz, CDCl3): δ 7.10-7.14 (m, 6H), 6.93-6.99 (t, 2H), 4.65-4.76 (q, 2H), 3.82-3.86 (t, 2H), 3.55-3.60 (dd, 2H), 3.17-3.25 (dd, 2H), 2.81-3.00 (m, 7H).