Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])=[CH:8][CH:9]=1
Reactant: NC(CO)CO
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(NC(CO)CO)ccc21
Yield: 10.4 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (200 mg, 0.59 mmol), serinol (217 mg, 2.3 mmol) and NMP (2 ml) gave title compound (25 mg, 54%) after purification by column chromatography using DCM/MeOH:aq.NH3 (99.5:0.5:1 drop) as the eluent.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]([N:27]([CH3:35])[CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:26])[CH:19]=2)=[C:13]([F:36])[CH:12]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:26])[N:27]([CH3:35])[CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[CH:19]=2)=[C:13]([F:36])[CH:12]=1
Reactant: [H][H]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
After dissolving (3-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamic acid benzyl ester (38.7 mg) in tetrahydrofuran (1.5 ml) and methanol (1.5 ml), 10% palladium-carbon (16 mg) was added under a nitrogen atmosphere. The atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 5 hours at room temperature. The catalyst was filtered and then washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of the title compound as a pale yellow oil (28.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([N:8]2[CH2:31][CH2:30][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>N1C=CC=CC=1>[CH3:32][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:7][C:6]=1[N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(C)c(N2CCc3nc(Nc4ccc(N5CCN(C)CC5)cc4)ncc3C2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (50.0 mg, 0.116 mmol) in Pyridine (1 ml) at 0° C. was added Butane-1-sulfonyl chloride (21.3 mg, 0.139 mmol) dropwise The reaction mixture was stirred for 15 minutes at 0° C. and then allowed to attain room temperature. It was then further stirred for 3 hours at room temperature. The reaction mixture was concentrated under vacuum. The reaction mass was then, diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with water, then with brine solution. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 50.4 mg (78.9%) Butane-1-sulfonic acid (4-methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-amide [49] as off white solid.
Reaction SMILES: CI.[N+:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:8][CH:7]=1)([O-])=O.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:20][N:11]([CH2:10][C:9]1[CH:18]=[CH:19][C:6]([NH2:3])=[CH:7][CH:8]=1)[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1
Reactant: O=[N+]([O-])c1ccc(CNC[C@H]2CCCO2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(Cc1ccc(N)cc1)C[C@H]1CCCO1
Reaction time: 4 h

Procedure:
Methyl iodide (0.728 mL, 11.7 mmol) was added to (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 40b (1.84 g, 7.80 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in DMF (30 mL). After 4 hrs, the reaction is was diluted with water and extracted with ethyl ether. The combined extracts are were washed with water, dried over MgSO4, and evaporated to prepare 1.43 g of methyl-(4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 150a. Using the procedure of Example 40, Compound 150a was used in place of (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 40b and carried forward to provide 4-({methyl-[(2R)-tetrahydro-furan-2-ylmethyl]-amino}-methyl)-phenylamine Compound 150b. Using the procedure of Example 1, 5-(5-chloro-2-methoxy-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5, 6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 147c was used in place of Compound 1 and Compound 150b was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 75. MS 579, 581 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:28][C@H:27]([C:29](O)=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@@H:25]4[CH2:26][C@H:27]([C:29]([NH:33][CH3:32])=[O:30])[CH2:28]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Product: CNC(=O)[C@H]1C[C@@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1

Procedure:
Following the general method as outlined in Example 61, starting from cis-3-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylic acid (Intermediate 36; 100 mg; 0.23 mmol), and MeNH2 (0.23 mL; 0.46 mmol; 2.0 M in THF), 100 mg (96%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]#[N:8])=O.CN1C(=O)N(C)CCC1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[N:34]3[N:35]=[C:36]([NH:39][CH:40]4[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]4)[CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1>C1COCC1.O.CC(=O)OCC>[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[N:34]3[N:35]=[C:36]([NH:39][CH:40]4[CH2:45][CH2:44][C:43](=[CH:6][C:7]#[N:8])[CH2:42][CH2:41]4)[CH:37]=[CH:38][C:33]3=[N:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a 0° C. solution of diethyl cyanomethyl phosphonate (0.07 mL, 0.4 mmol) in THF (1.5 mL) was added DMPU (0.27 mL, 1 mmol), followed by NaH (15 mL, 0.37 mmol). After stirring for 10 min, a solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (130 mg, 0.38 mmol) in THF (1.5 mL) was added. The resulting mixture was stirred at room temperature for 2 h. TLC (EA) showed most of s.m. was converted into product. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-(4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexylidene)acetonitrile (100 mg, 69%) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[N:20]4[CH:21]=[C:22]([S:25][C:26]5[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=5)[CH:23]=[CH:24][C:19]4=[N:18][N:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:36][C:37]([NH:39][C:40]1[N:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:43]=[C:42]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:41]=1)=O.CCN(C(C)C)C(C)C>CS(C)=O>[C:52]([C:42]1[CH:41]=[C:40]([NH:39][C:37]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([S:25][C:22]3[CH:23]=[CH:24][C:19]4[N:20]([C:16]([C:12]5[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)[CH:11]=5)=[N:17][N:18]=4)[CH:21]=3)=[CH:31][CH:30]=2)=[O:36])[N:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:43]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: Nc1ccc(Sc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)cc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Sc3ccc4nnc(-c5cccc(OCCN6CCOCC6)c5)n4c3)cc2)cc1
Yield: 40.9 %

Procedure:
A mixture of Example 10 step c (315 mg, 0.703 mmol), 5-(2,2,2-trichloroethoxycarbonyl)amino-3-tert-butyl-1-p-tolyl-1H-pyrazole (299 mg, 0.703 mmol) and DIPEA (116 μL, 0.675 mmol) in DMSO (3 mL) was heated at 55° C. for 24 h. The reaction was concentrated in vacuo and the residue purified by reverse phase preparative HPLC (Method 3) to afford the title compound (202 mg, 41%) as an off-white solid. LCMS (Method 4): Rt 8.46 min, m/z 703 [MH+]. 1H NMR (400 MHz, CDCl3): δ 9.30 (1 H, br s), 8.34 (1 H, br s), 8.16 (1 H, s), 7.49-7.41 (3 H, m), 7.37 (1 H, d, J 9.6), 7.29 (2 H, d, J 8.4), 7.25-7.20 (2 H, m), 7.18 (2 H, d, J 8), 7.09-7.04 (2 H, m), 6.90 (2 H, d, J 8), 6.44 (1 H, s), 4.15 (2 H, t, J 5.4), 3.72 (4 H, t, J 4.5), 2.88 (2 H, t, J 5.4), 2.64 (4 H, t, J 4.4), 2.11 (3 H, s), 1.30 (9 H, s).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([S:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=C1.S1C=CC(SC2C=C[C:23]([N+:26]([O-])=O)=[CH:22]C=2)=C1.NC1C=CC=CC=1>>[N:26]1[CH:23]=[CH:22][CH:5]=[CH:4][C:3]=1[S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccsc2)cc1
Reactant: Nc1ccc(Sc2ccsc2)cc1
Solvent: Nc1ccccc1
Product: Nc1ccc(Sc2ccccn2)cc1

Procedure:
4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B1. A13j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14](COC(=O)C(C)(C)C)[C:13](=[O:26])[NH:12][C:11]=2[N:10]=[C:9]1[N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1.Br[CH:41]1[CH2:44][CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([O:26][CH:41]3[CH2:44][CH2:43][CH2:42]3)=[N:12][C:11]=2[N:10]=[C:9]1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: BrC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c(OC2CCC2)nc2nc(N3CCNCC3)n(-c3ccccc3Cl)c12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8 mg of t-butyl 4-[7-(2-chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.3 ml of N,N-dimethylformamide, and 0.05 ml of bromocyclobutane and 20 mg of potassium carbonate were added thereto. The mixture was stirred at 50° C. overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic layer was concentrated. The residue was dissolved in methanol, and 5 mg of sodium hydride was added to the solution. The mixture was stirred at room temperature for three hours. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The solvent was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.89 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:22](=[O:23])[CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg 5-nitroindole are dissolved in 10 ml of tetrahydrofuran. 81 mg sodium hydride (60% in mineral oil) are added and the mixture is stirred for 1 hour at ambient temperature. Then 294 μl phenylacetic acid chloride are added dropwise and the mixture is stirred for another 3 hours. It is divided between saturated ammonium chloride solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:3).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1.Cl.[CH2:20]([S:22][C:23]1[C:31](O[C@@H]2CC[C@H](N)CC2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)[CH3:21].C(SC1C(O)=CC=C2C=1C=NN2)C>>[CH2:20]([S:22][C:23]1[C:31]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:3]2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)[CH3:21]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](O)C1
Reactant: CCSc1c(O[C@H]2CC[C@@H](N)CC2)ccc2[nH]ncc12
Agent: CCSc1c(O)ccc2[nH]ncc12
Agent: Cl
Product: CCSc1c(O[C@@H]2CCC[C@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12

Procedure:
The title compound was synthesized by carrying out reaction according to the method described in Example 610, except for using the trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 385, (b) and the 4-(ethylthio)-1H-indazol-5-ol obtained in Example 628, as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
A mixture of 5-bromopyridine-2-carboxylic acid (3.0 g), N,O-dimethylhydroxylamine hydrochloride (2.9 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.69 g), 1-hydroxybenzotriazole (4.01 g), N,N-diisopropylethylamine (12.97 mL), 4-dimethylaminopyridine (0.181 g) and DMF (37.1 mL) was stirred at room temperature for 5 hr, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23]/[N:24]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[CH3:12])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 80.8 %

Procedure:
3′,4′-Dimethoxyacetophenone (23) (150 g, 0.832 mmol) was condensed with compound 19 (187 mg, 0.914 mmol) according to the general procedure II-A defined above. After being heated for 3 h the mixture was cooled and the resulting solid filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30257 (222 mg, 81%) as a white solid, m.p. 118.4-121.0° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[NH:20][N:19]=1.Cl.O1CCOCC1>CN(C)C=O.O>[Cl:16][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:17][C:18]3[CH:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[NH:20][N:19]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: Nc1cc(CC(=O)O)[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(Nc2ncnc3cc(OCCCCl)ccc23)n[nH]1
Temperature: 90 °C
Yield: 81.9 %

Procedure:
4-chloro-7-(3-chloropropoxy)quinazoline (2.5 g, 9.72 mmol) and (3-amino-1H-pyrazol-5-yl)acetic acid (1.37 g, 9.72 mmol) were combined in dimethylformamide (25 ml). A solution of 4M HCl in dioxane (1.25 ml, 4.8 mmol) was added and the reaction heated to 90° C. for 40 minutes. The solution was cooled to room temperature, diluted with water (250 ml) and filtered through celite. The acidic solution was basified to pH 4.9 and the yellow powder filtered. (At pH 3, a red solid precipitated which was isolated, suspended in water and basified to pH 12. Careful adjustment back to pH 4.8 resulted in the precipitation of a yellow powder, which was combined with the first crop). The solid was washed with diethyl ether and dried over phosphorus pentoxide to yield (3-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)acetic acid as a pale orange solid (2.88 g, 82% yield):
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)c(Cl)ccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3ccc(Cl)c(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 7,8-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2.5 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed by crystallization from MeOH/EtOAc to give 1.5 g (81%) of a white solid: mp 132.5-135.0° C.; IR (diffuse reflectance) 2974, 1747, 1683, 1465, 1450, 1416, 1365, 1303, 1255, 1216, 1195, 1170, 1155, 1115, 803 cm−1; MS (EI) m/z 440 (M+), 442, 440, 386, 385, 384, 311, 300, 298, 57, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H, 5.98; N, 6.36.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13][C@@H:12]1[OH:34])=[O:4].[I-:35].[Na+]>CC(C)=O>[OH:34][C@@H:12]1[C@@H:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][I:35])[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13]1
Reactant: [I-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CI)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 87.7 %

Procedure:
2β-(4'-Chloroacetoxy-n-butoxy)-3α-hydroxy-5α-pregnane-11,20-dione (450 mg.) was dissolved in acetone (30 ml.) and sodium iodide (460 mg.) added to this solution. The mixture was refluxed for 1 hour, a white precipitate forming in this time. The mixture was filtered and the filtrate evaporated to a yellowish solid which was partitioned between ether and water. The ethereal solution was dried over anhydrous sodium sulphate and evaporated in vacuo to give the title compound (467 mg.) as a pale yellow foam which almost immediately collapsed to a gun. This unstable product was used immediately for the following Examples 50 and 51
Reaction SMILES: O1C2C=CC(O)=CC=2OC1.[O:11]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1.C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:37]1([CH:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46](=[O:53])[C:45]2=[O:54])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:55]1([CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([OH:53])([C:18]3[C:17]([OH:20])=[CH:16][C:15]4[O:11][CH2:12][CH2:13][C:14]=4[CH:19]=3)[C:45]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol (Foster et al., J. Chem. Soc. 1948:2254-2258) and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, the title compound was obtained (68%) as a white solid: MS (ES+) m/z 450.4 (M+1).