Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[NH:20][CH2:19][CH2:18][CH:17]4[OH:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1O>CO.C(Cl)Cl>[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1[O:24][CH:17]1[C:16]2[C:21](=[N:22][CH:23]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][CH:10]=3)[CH:15]=2)[NH:20][CH2:19][CH2:18]1
Reactant: CN1CCN(c2ccc(-c3cnc4c(c3)C(O)CCN4)cn2)CC1
Reactant: Oc1c(F)ccc(F)c1Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Oc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 54 %

Procedure:
6-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (85 mg) was reacted with 2-chloro-3,6-difluorophenol (50 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-10% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (54% yield). LCMS: m/z=472 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.89 (m, 1H), 2.21 (s, 3H), 2.24 (m, 1H), 2.39 (t, J=4.8 Hz, 4H), 3.40 (m, 1H), 3.47 (t, J=4.8 Hz, 4H), 3.63 (m, 1H), 6.82 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H) 7.25 (m, 1H), 7.39 (m, 1H), 7.52 (dd, J=2.5, 8.8 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H).
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[C:29]([F:41])=[CH:30][C:31]([F:40])=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:33]=2)[CH2:24][CH2:23]1>>[F:40][C:31]1[CH:30]=[C:29]([F:41])[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:3](=[O:5])[C:2]([OH:1])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:27][CH2:26]2)=[CH:33][C:32]=1[NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38]
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(O)(c3ccccc3)c3ccccc3)CC2)c(F)cc1F

Procedure:
Example 155 was prepared from hydroxy(diphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1 H), 8.39 (t, 1 H, J=8.4 Hz), 7.62–7.45 (m, 4 H), 7.38–7.18 (m, 7 H), 6.85–6.74 (m, 1 H), 5.43–5.14 (br, 1 H), 3.59–3.39 (m, 2 H), 3.11–2.97 (m, 2 H), 2.97–2.79 (m, 1 H), 2.59–2.45 (m, 2 H), 2.45–2.29 (m, 1 H), 2.14–1.86 (m, 4 H), 1.81–1.56 (m, 4 H), 1.01 (d, 6 H, J=7.2 Hz); ESMS m/e: 550.4 (M+H)+.
Reaction SMILES: [Cl-].[CH:2](=[N+:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[OH:25]>>[N:9]1([CH:2]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[OH:25])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: C(c1ccccc1)=[N+]1CCOCC1
Reactant: Oc1ccc2ccccc2c1
Agent: [Cl-]
Product: Oc1ccc2ccccc2c1C(c1ccccc1)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-benzylidene-morpholin-4-ium chloride and 2-naphthol.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][NH2:34])[CH2:26][CH2:25]2)=[CH:21][CH:20]=1.CO>ClCCl.C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:37]=[CH:36][C:22]([CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][NH:34][C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=3)[CH2:28][CH2:29]2)=[CH:21][CH:20]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.058 mmol) in dichloromethane (1 mL) was added to a mixture of 1-{4-chlorobenzyl)-4-((glycylamino)methyl}piperidine (0.050 mmol) and piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 mL). After the reaction mixture was stirred at room temperature for 2 h, methanol (1.0 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was loaded onto Varian™ SCX column, and washed with CH3OH (16 mL). Product was eluted off using 2 N NH3, in CH3OH (6 mL) and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(3,5-bis(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1213) (24.0 mg, 90%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 536.2 (M++H, C24H24ClF6N3O2).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.N12CCCN=C1C[CH2:18][CH2:17][CH2:16][CH2:15]2.C([OH:27])C>>[C:16]([C:17]1[O:1][C:2]2[C:3](=[O:13])[C:4]3[C:9]([C:10](=[O:12])[C:11]=2[CH:18]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)(=[O:27])[CH3:15]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCO
Product: CC(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Reaction time: 5 h

Procedure:
The synthetic process for preparing Crystal Form 3 is shown in FIGS. 6A-6D. The steps are outlined briefly herein. Step 1: 3-Butene-2-one (methyl vinyl ketone, MVK) is brominated using bromine. No additional solvent is used. The intermediate 3,4-dibromobutan-2-one is dissolved in tetrahydrofuran (THF) and reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form a second intermediate, 3-bromo-3-buten-2-one. Once this reaction is complete, 2-hydroxy-1,4-naphthoquinone (HNQ) is added. A second portion of DBU is added, and the mixture is exposed to air. The reaction is quenched with water and the solids are collected by filtration. These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol. The product is isolated by slurrying in ethanol and collecting the solids. Step 2: Residual amounts of the 2-acetyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione that accompany the desired 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (Compound 1) are oxidized to Compound 1 with activated manganese dioxide in toluene. The mixture is filtered through a cake of charcoal and Celite. The filtrate is concentrated to precipitate the product, which is filtered and dried. Step 3: The solids are slurried in ethyl acetate (25 mL/g purified Compound 1) at 75° C.-80° C. for about 5 hr, collected by filtration, and dried. Compound 1 produced with this method is Crystal Form 3. Compound 1 produced with this method without the slurry process yielded Crystal Form 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([Cl:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:28])[C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:14][C:11]([F:13])([F:12])[C:8]1[N:6]2[N:7]=[C:2]([N:25]3[CH2:26][CH2:27][N:22]([C:21]4[C:20]([Cl:28])=[CH:19][N:18]=[CH:17][C:16]=4[Cl:15])[CH2:23][CH2:24]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(c4c(Cl)cncc4Cl)CC3)nn12
Temperature: 70 °C
Yield: 29.3 %

Procedure:
A solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Examples 335-338, preparation of starting materials) (53 mg, 0.22 mmol) in ethanol (1 mL) was added to 1-(3,5-dichloropyridin-4-yl)piperazine (77 mg, 0.33 mmol). The reaction mixture was treated with DIPEA (43 mg, 0.33 mmol) and the mixture was heated at 70° C. for 4 hours. The reaction mixture was evaporated to leave an involatile residue that was purified by preparative reverse phase chromatography to give 3-[chloro(difluoro)methyl]-6-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine (28 mg, 29%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[NH4+].[OH-:13]>S(=O)(=O)(O)O>[NH:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[C:3]([C:1]([NH2:2])=[O:13])=[CH:4]1
Reactant: [OH-]
Reactant: N#Cc1c[nH]c2ncccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1c[nH]c2ncccc12
Yield: 91 %

Procedure:
A solution of 3-cyano-7-azaindole (3 g, 20.98 mmol) in concentrated sulfuric acid (50 mL) was stirred at room temperature for 1 h. The solution was slowly poured into ice and basified with concentrated NH4OH. The solution was concentrated under reduced pressure to produce brown residue which was extracted with acetone (4×100 mL). The organic extracts were dried and concentrated under reduced pressure to give title compound as a brown solid (3 g, 91%); Mass Spec.; MS 162 (M+1); 1H NMR (DMSO-d6; 500 MHz) 8.44(dd,1H),8.25(dd,1H), 8.14(s,1H), 7.45(brs,1H), 7.15(dd, 1H), 6.89(brs,1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>CO.C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1
Reactant: COC(=O)/C=C/c1ccc(F)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(c1ccc(F)cc1)C(C(=O)OC)C(=O)OC
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
Dimethyl malonate (14.7 g, 111 mmol) was added dropwise to the mixture of sodium methoxide in methanol (methanol solution 28%, 19.3 g, 100 mmol) and methanol (30 ml) under ice cooling and stirred for 15 minutes. To the mixture was added a solution of methyl (2E)-3-(4-fluorophenyl)-2-propenoate (10.0 g, 55.5 mmol) obtained in Reference Example 1 in THF (50 ml) under ice cooling and the mixture was refluxed for 12 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane/ethyl-acetate=8/1) to obtain 12.7 g (yield 73%) of 2-(4-fluorophenyl)-1,1,3-trimethoxy carbonyl propane via recrystallization (ethyl acetate-hexane). mp. 75–76° C.
Reaction SMILES: [C:1](O)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[O:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>C1(C)C=CC=CC=1>[C:1]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: c1ccoc1
Reactant: CCCCCCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 91 %

Procedure:
In 50 ml of toluene were dissolved 6.51 g (0.05 mole) of heptanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 4.43 g (0.065 mole) of furan and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 5.5 hours. After completion of the reaction, the reaction solution was cooled and washed with 5% aqueous sodium carbonate solution and water in this order. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 8.2 g of 2-heptanoylfuran.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]([CH3:19])[CH2:16][CH2:17]O)=[CH:13][C:8]=2[O:7][CH2:6]1>C(Cl)Cl>[ClH:3].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]([CH2:16][CH2:17][Cl:3])[CH3:19])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)Cc1ccc2c(c1)OCO2
Solvent: ClCCl
Product: CN(CCCl)Cc1ccc2c(c1)OCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
Thionyl chloride (60 mL) is added dropwise over 30 minutes to a 0° C. solution of 2-(benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-ethanol (22.2 g, 110 mmol) in DCM (250 mL) under nitrogen. The ice bath is removed, and the solution is stirred at room temperature overnight (16 h). The white slurry is concentrated under reduced pressure, diluted with brine (150 mL) and ethyl acetate (200 mL), and the precipitate is collected via vacuum filtration. The solid is washed with ethyl acetate and dried overnight under vacuum to afford 26.5 g (91%) of benzo[1,3]dioxol-5-ylmethyl-(2-chloro-ethyl)-methyl-amine hydrochloride as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[CH2:10]1[O:14][CH:11]1[CH2:12][CH3:13].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]([OH:14])[CH2:12][CH3:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCC1CO1
Reactant: CCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(OCC(O)CC)cc1
Yield: 76.2 %

Procedure:
In a closed vessel 12.2g (0.1 mol) of p-ethylphenol, 7.2 g (0.1 mol) of 1,2-butylene oxide and 0.8 ml of a 50% aqueous solution of sodium hydroxide were heated at 140° to 145° C for 4 hours in the same way as in Example 1. The reaction mixture obtained was treated in the same way as in Example 1 to afford 14.8 g of 1-(p-ethylphenoxy)-butan-2-ol (compound No. 52) in a yield of 76.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[Li]C(C)(C)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](OCC)=[O:30])=[N:27][CH:28]=1.O>CCOCC.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:30])=[N:27][CH:28]=1
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(Cl)cn1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ccc(Cl)cn2)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 57.4 %

Procedure:
To a cold (−23° C.), stirred solution of tert-butyl 2-methoxyphenylcarbamate (548 mg, 2.454 mmol) in ether (6 mL) under N2 was added t-BuLi (3.2 mL, 5.44 mmol). After stirring for 2.5 h, the reaction mixture was cooled to −78° C. To the reaction mixture was added a solution of ethyl 5-chloropicolinate (564.5 mg, 3.04 mmol) in ether (12 mL) dropwise via cannula over 5 min. The reaction mixture was stirred for 60 min, and then warmed to room temperature. After 1.5 h, to the reaction mixture was added H2O with vigorous stirring. The reaction mixture was diluted with EtOAc, and the organic phase was separated, washed with sat NaCl then dried (Na2SO4), filtered and concentrated to yield the product Intermediate A-29A (511.5 mg, 57.4% yield)) as a yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (1 H, dd, J=2.3, 0.6 Hz), 8.08 (1 H, dd, J=8.4, 0.7 Hz), 7.80 (1 H, dd, J=8.4, 2.4Hz), 7.16-7.25 (2 H, m), 7.06 (1 H, dd, J=7.5, 2.2Hz), 6.90 (1 H, s), 3.92 (3 H, s), 1.28 (9 H, s).
Reaction SMILES: CC1C=CC([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=C(C=1)C(O)=O.[F:16][C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19](I)[CH:18]=1.N1C=CN=N1>>[F:16][C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:18]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)c(F)cc1I
Agent: c1c[nH]nn1
Product: O=C(O)c1cc(F)c(F)cc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4,5-difluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 226 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>CC(C)=O.C1(C)C=CC=CC=1>[CH2:22]([O:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:21]#[CH:20]
Reactant: CCCc1cc2c(cc1O)OCO2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc2c(cc1CCC)OCO2

Procedure:
Following the same procedure as in Example 3 a) and b), but using 7.2 g (0.04 moles) of 5-hydroxy-6-propyl-benzo[1.3]dioxole, 5.92 g (0.04 moles) of anhydrous potassium carbonate in 40 ml of acetone were reacted with 5.95 g (0.04 moles) of a solution of propargyl bromide in toluene, (80% w/w).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:31][OH:32].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN([CH:65]=[O:66])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:31]([O:66][CH3:65])=[O:32])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 70 °C
Yield: 93 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example No. 40 (30.0 g), Et3N (19.1 mL), MeOH (110.6 mL), Pd(OAc)2 (431 mg), and 1,3-bis (diphenylphosphino) propane (791.9 mg) in 375 mL anhydrous DMF is stirred at room temperature until everything dissolves. CO(g) is slowly bubbled through for 2 days and the reaction is maintained at 70° C. The reaction is cooled to room temperature. The product is precipitated by adding 160 mL 1N HCl to the reaction mixture. An orange solid precipitates and is collected. The solid is triturated with EtOAc, filtered, and washed with CH2Cl2 to afford 23.8 g (93%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:35][CH:36]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:37]1=[O:51]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:35][CH:36]1[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:37]1=[O:51])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)CN1C(=O)C(N)Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 18 h

Procedure:
5-Chloro-1H-indole-2-carboxylic acid (493 mg, 2.52 mmol), HOBT (340 mg, 2.52 mmol), DCM (100 mL) and finally EDCI (483 mg, 2.52 mmol) were added to methyl 2-(3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (Method 1; 590 mg, 2.52 mmol) and the reaction was stirred for 18 h. The reaction was then diluted with water (50 mL) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with Et2O (2×20 mL). After filtration the resultant solid was then triturated with refluxing Et2O (25 mL) and after cooling the title compound (608 mg, 59%) was collected again by filtration as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:34])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:34])[C:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2.3 g, 7.9 mmol) prepared in Example 26a, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in 1,2-dichloroethane (130 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2.7 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (538 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.[CH3:35]N(C)C1CCNC1>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:5][CH2:1][CH:2]([N:7]([CH3:6])[CH3:35])[CH2:3]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using dimethyl-pyrrolidin-3-yl-amine in place of 2,6-dimethyl-piperazine. The title compound was obtained as a white solid (21.8 mg, 36%).