Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[S:6][C:7]([C:9]3[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:20][O:19][C:18]1[C:2]([O:1][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:3][C:4]2[CH:8]=[C:7]([C:9]3[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=3)[S:6][C:5]=2[CH:17]=1
Reactant: COc1cc2sc(C3=NNC(=O)CC3C)cc2cc1O
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2sc(C3=NNC(=O)CC3C)cc2cc1OCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture of 4,5-dihydro-6-(5-hydroxy-6-methoxybenzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone (1.0 g), anhydrous potassium carbonate (1.0 g) and 1-(3-chloropropyl)piperidine hydrochloride (0.72 g) in dimethyl formamide (12 ml) was stirred at room temperature for 3 days. The mixture was then warmed to 65° C. and, after a further 2 hours, more anhydrous potassium carbonate (0.50 g) and 1-(3chloropropyl)piperidine hydrochloride (0.36 g) were added. After a further 2 hours the reaction mixture was cooled to room temperature and poured into water (60 ml). The product, which precipitated as a gum, was isolated by decantation and then crystallized from ethyl acetate to give 4,5-dihydro-6-(6-methoxy-5-[3-(piperidin-1-yl)propyloxy]-benzo[b]thien-2-yl)-5-methyl-3(2H)-pyridazinone as a white solid (0.90 g), m.p. 198°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[Na+].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]I)=[C:29]([Cl:36])[CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:5]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])([C:4]([O:3][CH2:1][CH3:2])=[O:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:29]([Cl:36])[CH:28]=1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: Clc1cc(Br)ccc1CCI
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccc(Br)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
Diethyl(tert-butoxycarbonyl)aminomalonate (202 g) was dissolved in a mixed solution of tetrahydrofuran (6000 mL) and N,N-dimethylformamide (714 mL), and sodium tert-butoxide (70.5 g) was added. After heating the mixture to the refluxing temperature, a solution of 2-(4-bromo-2-chlorophenyl)ethyl iodide (246 g) of Reference Example 18 in tetrahydrofuran (940 mL) was added to the reaction mixture, and the mixture was refluxed with stirring for 15 hr. After cooling, the reaction mixture was poured into 25% aqueous citric acid solution. After partitioning and extraction with ethyl acetate, the organic layer was washed with water and 25% brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (227 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[N:32]1(C(OC(C)(C)C)=O)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:59]CCl>>[ClH:59].[ClH:59].[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNCC3)c2c1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product of Example 75 step i) (400 mg) in dichloromethane (20 mL) was added piperazine-1-carboxylic acid, tert-butyl ester (534 mg) and the mixture stirred at room temperature for 10 minutes before the addition of sodium triacetoxyborohydride (608 mg). After stirring at room temperature for a further 24 hours the reaction mixture was diluted with dichloromethane and washed with water. The organic phase was then evaporated to dryness and the residue treated with 4M HCl in 1,4-dioxane (10 mL) with methanol being added to aid dissolution. The reaction was stirred at room temperature for 1 hour and then concentrated to dryness. The residue was stirred in methanol and the resulting precipitate collected by filtration, washing with methanol to give the title compound as a solid (190 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]([NH2:18])=[O:17])[CH:13]=2)[NH:8][CH:7]=1.[Cl:19][CH2:20][CH2:21][N:22]([CH2:31][CH2:32]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[N:30]>CC(C)=O.O>[ClH:19].[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:22]1[CH2:31][CH2:32][N:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]([NH2:18])=[O:17])[CH:13]=3)[NH:8][CH:7]=2)[CH2:20][CH2:21]1)#[N:30]
Reactant: NCCCCc1c[nH]c2ccc(NC(N)=O)cc12
Reactant: N#Cc1ccccc1N(CCCl)CCCl
Solvent: CC(C)=O
Solvent: O
Product: Cl
Product: N#Cc1ccccc1N1CCN(CCCCc2c[nH]c3ccc(NC(N)=O)cc23)CC1
Reaction time: 24 h

Procedure:
A mixture of 2.87 g of 3-(4-aminobutyl)-5-indolylurea [obtainable from 5-indolylurea via 3-(4-chlorobutyryl)-5-indolylurea, 3-(4-chlorobutyl) -5-indolylurea and 3-(4-phthalimidobutyl)-5-indolylurea] and one equivalent of N,N-bis(2-chloroethyl)-o-cyanoaniline ("C") in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up in a conventional manner. 3-[4-(4-o-Cyanophenylpiperazino)butyl]-5-indolylurea, hydrochloride, m.p. 164°-166° is obtained.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[OH-:29].[Na+].[C:31]([OH:35])(C)(C)C>O1CCOCC1>[C:22]1([N:21]2[C:17]([C:15]3[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][CH:4]=[CH:5][C:6]=4[C:31]([OH:35])=[O:29])[N:16]=3)=[CH:18][CH:19]=[N:20]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(Nc2nccc(-c3ccnn3-c3ccccc3)n2)cc1
Reactant: CC(C)(C)O
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1Nc1nccc(-c2ccnn2-c2ccccc2)n1
Temperature: 80 °C

Procedure:
A mixture of methyl 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino}benzoate (2-1, 60 mg, 0.16 mmol, 1 equiv) and aqueous 1N sodium hydroxide solution (0.81 mL, 0.81 mmol, 5.0 equiv) in a 1:1 mixture of t-butanol and dioxane (5 mL) was heated at 80° C. for 16 hours. The reaction mixture was partitioned between aqueous half-saturated ammonium chloride solution and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino}benzoic acid (2-2) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.50 (br s, 1H), 10.04 (s, 1H), 8.60 (d, 1H, J=4.9 Hz), 7.86 (s, 1H), 7.63 (d, 2H, J=8.2 Hz), 7.51–7.33 (m, 5H), 7.25 (d, 2H, J=8.6 Hz), 7.06 (m, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])=[CH:36][CH:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (34%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:31])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:30])[CH2:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:5][CH:4]=1)#[N:2].[ClH:32].C(=O)([O-])[O-].[NH4+:37].[NH4+]>C(O)C>[Cl-:32].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][C:11](=[O:31])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:30])[CH2:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:7][CH:8]=1)(=[NH:37])[NH2:2]
Reactant: CS(=O)(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Reactant: [NH4+]
Reactant: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CS(=O)(=O)NC1CCCC[C@@H]1CC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C(=N)N)cc1
Product: [Cl-]
Reaction time: 48 h
Yield: 73 %

Procedure:
To a solution of the compound (18.6 g, 42 mmol) obtained in the item (d) inchloroform (100 ml), a 37% hydrochloride in ethanol (100 ml) is added at 0° C. The mixture is allowed to stand at 0° C. for 48 hours and then the solvent is evaporated. The resulting residue is dissolved in methanol (100 ml) and ammonium carbonate (16 g, 166 mmol) is added at 0° C. After stirring for 6 hours, the solvent is evaporated and theresulting residue is purified with silica gel chromatography (chloroform-methanol) to give 5.2 g of the titled compound (73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].[F:14][C:15]1[C:16](I)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])/[C:18]/2=[CH:25]\[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[C:21]2[C:17]=1/[C:18](=[CH:25]/[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31])/[C:19](=[O:24])[NH:20]2)[CH3:2]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCC(NC(C)=O)C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)NC(C)=O

Procedure:
Using Method C above, 2-(acetylamino)-4-pentynoic acid ethyl ester (92.6 mg, 0.51 mmol) (Bachem) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give rac-(Z)-2-(acetylamino)-5-[5-fluoro-2,3,dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid ethyl ester. (Yield 70 mg, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3 g, 9.76 mmol) and 10% palladium on carbon (300 mg) in 50 mL ethanol and 20 mL ethyl acetate was hydrogenated at room temperature under a 50 psi hydrogen atmosphere for 2 hrs. The reaction mixture was filtered through a plug of Celite and evaporated under reduced pressure to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30]I>>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)Cc1ccccc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCCl)c1ccccc1
Yield: 97.8 %

Procedure:
Step AAO (1): 2-Phenylacetic acid (2.19 g, 16.1 mmol) was deprotonated with NaHMDS 2.0 M in THF (18.1 mL, 36.2 mmol) and reacted with 1-chloro-4-iodobutane (3.87 g, 17.7 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-phenylhexanoic acid (3.57 g, quantitative yield) as a pale yellow oil. LC-MS (M−H)− 225.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.25-7.39 (5 H, m), 3.58 (1 H, t, J=7.6 Hz), 3.52 (2 H, t, J=6.7 Hz), 2.12 (1 H, dddd, J=13.4, 10.5, 7.8, 5.5 Hz), 1.73-1.90 (3 H, m), 1.34-1.54 (2 H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:10])[CH3:9].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([OH:21])[CH:15]=1.O>CN(C)C=O.C(OC(=O)C)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[C:16]([O:21][CH:8]([CH3:10])[CH3:9])[CH:15]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1cc(O)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cc(OC(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
After adding 298 mg (2.16 mmol) of potassium carbonate and 0.12 ml (1.29 mmol) of 2-bromopropane to a solution of 120 mg (0.43 mol) of 3-hydroxy-5-iodobenzoic acid methyl ester in N,N-dimethylformamide (4.0 ml), the reaction mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain 133 mg of 5-iodo-3-isopropoxybenzoic acid methyl ester (yield: 96%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.CC[N:17]([CH:21]([CH3:23])[CH3:22])C(C)C.O.CN1C(=O)C[CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:17][C@@H:21]([CH:22]3[CH2:28][CH2:27]3)[CH3:23])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CN1CCCC1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (2.0 g, 7.29 mmol), (R)-1-cyclopropylethanamine, HCl (0.975 g, 8.01 mmol) and DIPEA (2.99 mL, 17.12 mmol) in NMP (Volume: 15 mL) was heated to 100° C. for 4 hr. The reaction mixture was added 60 mL of water and stirred for 10 minutes. The solid was collected as the desired product (1.85 g, 79% yield). 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 3.92 (quin, J=6.4 Hz, 1H), 1.40 (d, J=6.4 Hz, 3H), 1.18-1.05 (m, 1H), 0.65-0.49 (m, 2H), 0.41-0.30 (m, 2H). MS (ES+) m/z: 323.1, 325.1 (M+H); HPLC: 93%, retention time: 3.318 min (analytical HPLC Method B).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33]>>[CH3:31][C:32]([NH:40][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33]
Reactant: CC(C)(N)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 75 %

Procedure:
A procedure similar to that described in Example 3(b) was repeated, except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-methyl-1-phenylethylamine were used as starting materials, in relative proportions similar to those used in that Example, to give the title compound in a yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:22])=[C:6]2[C:11]=1[C:10]1=[N:12][CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[C:15](=[O:16])[N:9]1[CH:8]=[CH:7]2>C(O)(=O)C.Cl.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:22])=[C:6]2[C:11]=1[C:10]1=[N:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[C:15](=[O:16])[N:9]1[CH:8]=[CH:7]2
Reactant: CCOC(=O)c1cnc2c3c(N)ccc(Br)c3ccn2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)c2ccn3c(=O)c(C(=O)O)cnc3c12
Temperature: 80 °C
Yield: 39 %

Procedure:
A suspension of ethyl 11-amino-8-bromo-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (500 mg), in a mixture of acetic acid (25 ml) and 36% hydrochloric acid (5 ml) was heated at 80° C. for 3 hours. The mixture was cooled and diluted with water. The precipitated solid obtained was collected and dissolved into N,N-dimethylformamide (30 ml). The solution was added to an aqueous sodium bicarbonate solution (15 ml). The resulting precipitate was collected, and then dissolved in N,N-dimethylformamide (130 ml). The solution was filtered for removal of insoluble materials. The filtrate obtained was acidified with acetic acid to give 11-amino-8-bromo-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (180 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:10]=2)=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([O:28][C:29](=[O:32])[CH2:30]Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=3[O:24][CH3:25])=[CH:14][CH:13]=2)[CH:18]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
To a vial containing 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine (0.35 g, 1.0 mmol) dissolved in acetonitrile (1 mL) was added bromo-acetic acid ethyl ester (0.113 ml, 1.0 mmol) and potassium carbonate (167 mg, 1.2 mmol) and additional acetonitrile (5 mL). The vial was sealed and heated to 80° C. overnight. The reaction was partitioned between ethyl acetate (200 mL) and aqueous HCl (0.1 M, 200 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (200 mL). The organic layers were washed with brine (100 mL), combined, dried over magnesium sulfate, concentrated, dissolved in a minimal amount of dichloromethane and purified by flash chromatography with a 0-30% ethyl acetate in hexanes gradient to yield [3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamino]-acetic acid ethyl ester as a clear semisolid (190 mg, 44%). LC-MS (ES) calculated for C24H23F2NO4, 427.16; found m/z 428 [M+H]+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O.C(OCC)(=O)C>ClCCl>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][S:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])(=[O:10])=[O:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1ccccc1CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccccc2C)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.00 g of o-tolylmethanesulfonyl chloride was initially charged in 30 ml of dichloromethane, and 1.46 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of ethyl acetate, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.42 g) was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH2:18][OH:19])[NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2cc(OCc3ccccc3)cnc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2cc(OCc3ccccc3)cnc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
The suspension of 0.3 g (1.2 mmol) (5-benzyloxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-methanol and 0.82 g (9.4 mmol) manganese dioxide in 15 ml dichloromethane was stirred 3 h at room temperature. After filtration over Dicalite Speed Plus® (Aldrich) the solvent was evaporated to give 0.22 g (74%) of the desired compound as a light brown solid.
Reaction SMILES: C(N1CCC(C2C=CC(N[C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[C:28](=[O:32])[NH:27][CH2:26]5)=[CH:21][N:22]=3)=CC=2)CC1)(C)C.[CH:36]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][C:46]=2[C:52]([F:55])([F:54])[F:53])[CH2:41][CH2:40]1)([CH3:38])[CH3:37]>>[CH:36]([N:39]1[CH2:40][CH2:41][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[C:28](=[O:32])[NH:27][CH2:26]5)=[CH:21][N:22]=3)=[CH:47][C:46]=2[C:52]([F:55])([F:54])[F:53])[CH2:43][CH2:44]1)([CH3:38])[CH3:37]
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2)CC1
Reactant: CC(C)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2C(F)(F)F)CC1

Procedure:
This compound may be prepared using the methods as described for Compound 206, using 4-(4-isopropylpiperazin-1-yl)-3-(trifluoromethyl)phenylamine in Step 3. LCMS: Rt=0.98 min (95%), m/z 536 (M+H)+.