Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.Cl.[C:25](O)(=O)[CH3:26]>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:25]([CH3:26])=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc2c(ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc32)[nH]1
Temperature: 120 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (80 mg, 0.243 mmol) is dissolved in glacial acetic acid (1.5 ml), dilute hydrochloric acid (2M, 0.1 ml) is added, and the mixture is heated at 120° C. for 90 min. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (3×40 ml), water (40 ml) and saturated brine (40 ml). The organic layer is dried (MgSO4), filtered and evaporated to give a brown solid. This is triturated with ethyl acetate containing a few drops of methanol and filtered to give a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: Clc1cc(Nc2ccccc2)ncn1
Temperature: 84 °C
Yield: 40 %

Procedure:
250 mg of 4,6-dichloropyrimidine and 120 mg of aniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl was added. The mixture obtained was refluxed (84° C.) for 2.5 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-phenylpyrimidin-4-amine hydrochloride in the form of colorless crystals was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.CC(C)([O-])C.[K+].[CH3:24][C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[CH:27]=[CH2:28].C(OCC)(=O)C>CS(C)=O.Cl.C(OCC)C>[CH3:24][C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[CH2:27][CH2:28][N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)C(C)(C)C
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)CCn1c(-c2cccnc2)cc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 0.225 g, 1.026 mmol) in DMSO (5 mL) is added potassium tert-butoxide (0.182 g, 1.53 mmol) and the mixture is stirred at room temperature for 0.5 h. 4,4-Dimethyl-pent-1-en-3-one (0.345 g, 3.078 mmol) is added and the mixture is stirred at 50° C. overnight. Dilution with ethyl acetate gives a solution which is washed with water twice, dried over sodium sulfate and concentrated in vacuo. The residue is purified by Xbridge Shield RP18 with a gradient of acetonitrile in 0.1% NH4OH to give an oil. Addition of diethyl ether and a few drops of concentrated HCl, followed by lyophilization affords 1-(4,4-dimethyl-3-oxo-pentyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile as a light yellow color solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 0.90 (s, 9H), 2.94 (t, J=6.4 Hz, 2H), 4.61 (t, J=6.6 Hz, 2H), 6.88 (s, 1H), 7.59 (dd, J=8.7, 1.6 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.93 (dd, J=8.0, 5.4 Hz, 1H), 8.10 (d, J=1.0 Hz, 1H), 8.44 (dt, J=7.9, 1.7 Hz, 1H), 8.82 (dd, J=5.3, 1.3 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 332.1762 [(M+H)+ Calcd for C21H22N3O: 332.1763].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[C:19]([C:21]1[CH:29]=[CH:28][C:24](C(Cl)=O)=[CH:23][CH:22]=1)#[N:20].[C:30]1([NH2:37])[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[NH:36]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:37]=[C:16]1[C@@H:9]1[CH2:10][C:11](=[CH:13][C:14]#[N:15])[CH2:12][N:8]1[C:6]([C:24]1[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:29][CH:28]=1)=[O:7]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: Nc1ccccc1N
Product: N#CC=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)c2ccc(C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1,2-benzenediamine the title compound was obtained in 84% purity by LC/MS. MS(ESI+): m/z=354.2.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][Mg]Cl.COC1C=C(C=CC=1)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COc1ccc(C[Mg]Cl)cc1OC
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(OC)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(OC)c(OC)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3,4-dimethoxy-benzylmagnesium chloride (0.25 M in THF, 28.0 mL, 7.0 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3,4-dimethoxybenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound: 0.050 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.06-2.18 (m, 1H) 2.50-2.68 (m, 3H) 2.68-2.81 (m, 2H) 3.20-3.35 (m, 1H) 3.74-3.94 (m, 9H) 6.36-6.46 (m, 1H) 6.69 (d, J=1.76 Hz, 1H) 6.74 (dd, J=8.10, 1.56 Hz, 1H) 6.82 (d, J=8.10 Hz, 1H) 8.80 (br. s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[C:17]2[CH:24]=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:19]1[C:18]2[NH:22][CH:23]=[CH:24][C:17]=2[C:16]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[N:21][CH:20]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2ncnc3[nH]ccc23)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl piperidin-3-ylcarbamate compound (5.0 g, 25 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.75 g, 25 mmol) in DMF (50 mL) was added DIEA (4.2 mL, 3.1 g, 25 mmol) and the solution was stirred at 100° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate. To a solution of tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate (6.3 g, 20 mmol) in dioxane (50 ml) was added 4.0 N HCl (50 mL, 200 mmol) and stirred at rt. After several hours, the reaction mixture was concentrated in vacuo to give compound 33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14](O)[C:13]([C:19]([NH2:21])=O)=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>CC#N>[Cl:24][C:14]1[C:13]([C:19]#[N:21])=[N:12][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16](=[O:17])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-n2nc(C(N)=O)c(O)cc2=O)cc1OC
Solvent: CC#N
Product: COc1ccc(-n2nc(C#N)c(Cl)cc2=O)cc1OC
Reaction time: 19 h

Procedure:
The starting amide (30) (190 mg) was dissolved in 1 ml of CH3CN, treated with 1 ml of phosphorus oxychloride, and heated to reflux. After 18-20 hours the reaction was complete by HPLC. The reaction mixture was poured into ice and stirred for one hour. The product was extracted with ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. This material was then purified by normal phase column SiO2 chromatography affording 90 mg of desired nitrile chloride (31) as a solid. MS+: m/e=292.0 (M+H), 1H-NMR (500 MHz, MeOH-d4): d 7.40 (s, 1H), 7.18 (s, 1H), 7.12 (d, 1H), 7.08 (d, 1H), 3.90 (s, 3H), 3.85 (s, 3H), ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: BrCCCCBr
Reactant: CSc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(OCCCCBr)cc1
Reaction time: 16 h

Procedure:
7.0 g (0.05 mol) of 4-(methylthio)phenol are stirred in 80 cc of absolute dimethylformamide for 30 minutes with 2.8 g (0.05 mol) of pulverized potassium hydroxide. 16.2 g (0.075 mol) of 1,4-dibromo butane are added dropwise over the course of 15 minutes and the mixture is stirred at 20° for 16 hours. After the addition of approximately 150 cc of water, the reaction mixture is extracted with ether, the extract is washed with ice-cold 1N sodium hydroxide solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated. After chromatography of the residue on silica gel with hexene/ethyl acetate (99:1) and (98:2) and subsequent crystallization from petroleum ether, pure 1-(4-bromo-butyloxy)-4-(methylthio)-benzene is obtained. M.P.: 33°-34° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.[C:44](O)(=[O:55])[CH2:45][C:46](CC(O)=O)([C:48](O)=[O:49])O>C1COCC1.C(Cl)Cl>[CH:11]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:9]=1[O:10][C:44](=[O:55])[CH2:45][CH2:46][C:48]([NH:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:49])([CH3:13])[CH3:12]
Reactant: NCCN1CCCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)CCC(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of propofol hemisuccinate (2.0 g, 7.2 mmol) in THF—CH2Cl2 (1:1, 60 mL) was added EDCl (1.72 g, 9 mmol) followed by HOBt (1.37 g, 9 mmol). The reaction mixture was stirred at ambient temperature for 15 min and 1-(2-aminoethyl)pyrrolidine (0.912 g, 8 mmol) was added and stirring was maintained overnight. 10% aqueous citric acid (50 ml) was added and the mixture was extracted with CH2Cl2 (100 ml×2). The organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed and the product was purified by silica gel column chromatography using acetone with 1% Et3N. Removal of the solvent gave the product as an oil. Yield: 2.47 gram (92%)
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[CH:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@H:12]2[C@@H:15]([O:17][S:33]([CH3:32])(=[O:35])=[O:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)O)[C@H]2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e10) (80 mg) was treated with methanesulphonyl chloride and triethylamine in dichloromethane as described in Example 1. After work-up, evaporation of the dichloromethane solution afforded p-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e11) as a pale-yellow foam (67 mg); νmax (CH2Cl2) 1780, 1700, 1675, 1425, 1245 and 1175 cm-1.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:17][CH2:18][C:19](O)=[O:20].[NH2:22][C:23]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:24]=1[C:25](=[N:32][CH:33]([CH3:36])[CH2:34][OH:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O.O.O1CCCC1>[NH2:17][CH2:18][C:19]([NH:22][C:23]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:24]=1[C:25](=[N:32][CH:33]([CH3:36])[CH2:34][OH:35])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:20]
Reactant: NCC(=O)O
Reactant: CC(CO)N=C(c1ccccc1)c1cc(Cl)ccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(CO)N=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)CN
Yield: 32.9 %

Procedure:
To a solution of 4.5g of N,N'-dicyclohexylcarbodimide in 100ml of dimethylformamide is added a solution of 2.2g of glycine hydrochloride in 2.2ml of water in a period of about 30 seconds under stirring and ice-cooling. To the reaction mixture is immediately added dropwise a solution of 3.3g of 2-[(2-amino-5-chloro-α-phenylbenzylidene)amino]propanol in 10ml of tetrahydrofuran and the mixture is stirred for further 3 hours at room temperature. After the reaction is completed, the reaction mixture is treated by the same manner as described in the Example 1 to give 1.3g of the desired product melting at 168°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:10].OS(O)(=O)=O.[N+]([C:19]1[CH:20]=C(S(O)(=O)=O)C=C[CH:24]=1)([O-])=O>OCC(CO)O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][C:4]=1[CH3:10])[N:7]=[CH:20][CH:19]=[CH:24]2
Reactant: COc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: COc1cc2cccnc2cc1C
Temperature: 140 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To 4-methoxy-3-methylaniline (6.7 g) was added concentrated H2SO4 (12.4 mL), followed by glycerin (21.1 g), m-nitrobenzenesulfonic acid (6.53 g), H3BO3 (3.4 g) and FeSO47H2O (3.2 g). The mixture was stirred at 140° C. for 1 h. The reaction was cooled to 25° C., quenched with ice-water and neutralized with 30% KOH. The mixture was extracted with DCM (2×), and the combined extracts dried with Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc) to give 6-methoxy-7-methylquinoline (4.3 g) LCMS-ESI+ (m/z): 174.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][N:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][N:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COc1cc(C(=O)Nc2ccccc2)ccn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccnc(O)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 2-methoxy-N-phenylisonicotinamide (1.00 g, 4.38 mmol) in anhydrous chloroform (60 mL) was added iodotrimethylsilane (17.50 g, 87.50 mmol). The reaction mixture was stirred at reflux for 16 hours. After cooling to ambient temperature, methanol (10 mL) was added dropwise to quench the reaction. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate in vacuo. The brown crude product was recrystallised from ethyl acetate and methanol to afford the title compound as a colourless solid (0.35 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 10.31 (s, 1H), 7.73-7.68 (m, 2H), 7.47 (d, J=6.8 Hz, 1H), 7.31 (t, J=7.9 Hz, 2H), 7.10-7.05 (m, 1H), 6.81 (s, 1H), 6.49 (dd, J=6.8, 1.7 Hz, 1H); MS (ES+) m/z 215.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10](C(=O)C)[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)n1ncc2ncc(Br)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Brc1cnc2cn[nH]c2c1
Reaction time: 5 h
Yield: 85.6 %

Procedure:
To a solution of 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 5.9 mmol) in tetrahydrofuran (20 mL) and methanol (15 mL) was added a solution of sodium hydroxide (0.71 g, 18 mmol) in water (5 mL) at 27° C. After 5 h, the reaction was neutralized with hydrogen chloride acid (2 mol/L, 10 mL), and the resulting mixture was extracted with ethyl acetate (3×50 mL). The collected organic extracts were concentrated in vacuo. Purification by flash column chromatography (15→30% ethyl acetate in petroleum ether) afforded 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.0 g, 86% yield). 1H NMR (400 MHz, Chloroform-d) δ 10.46 (brs, 1 H), 8.58 (s, 1 H), 8.25 (s, 1 H), 7.98 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>ClCCl.[Cl-].[Na+].O>[Cl:14][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
4-methoxy-phenethyl alcohol (15.2 g, 10 mmol) were dissolved in 200 ml of dichloromethane and at 0° C., 7.35 ml of thionyl chloride were added. The reaction mixture was allowed to warm to room temperature over 1/2 hour. After stirring for 20 hours, the mixture was added to brine and extracted with dichloromethane. The dichloromethane was evaporated to obtain an oil which was chromatographed on silica gel using a mixture of 30% ethyl acetate/hexane as the eluent to obtain 8.8 g (51%) of the title product.
Reaction SMILES: ClC1C=CC=CC=1C=O.CC1C=CN=CC=1.C(OC(=O)C)(=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=1
Reactant: Clc1ccccc1C=Cc1ccncc1
Agent: O=Cc1ccccc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccncc1
Product: Clc1ccccc1CCc1ccncc1

Procedure:
14.1 g. (0.1 mole) of 2-chlorobenzaldehyde and 9.4 g. (0.1 mole) or 4-methylpyridine are refluxed for six hours in 40ml. of acetic anhydride. The reaction mixture is concentrated in vacuo and then dissolved in 200 ml. of chloroform. The chloroform solution is washed with aqueous sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. The oily residue is dissolved in isopropanol and treated with HCl in isopropanol until acidic. The crystalline hydrochloride salt is filtered, dissolved in 150 ml. of water and neutralized with aqueous sodium bicarbonate. The product is extracted with chloroform to yield 12.6 g. of oil 4-[2-(2-chlorophenyl)ethenyl]pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].COCCO.Cl>C(O)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:18]3[CH2:19][CH2:20][CH2:21][O:17]3)=[O:23])[CH2:25][CH2:26]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 70 °C
Yield: 93.1 %

Procedure:
A slurry of 60 grams (0.25 mol) of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 55.3 g (0.3 tool) of 1-(2-tetrahydrofuroyl)piperazine and 175 grams of 2-methoxyethanol was heated, under a nitrogen atmosphere with mechanical stirring, to 120°-123° C. for eight hours. The slurry was then cooled to 70° C. and 140 ml of 3A 200 proof ethanol was added. The resulting mixture was heated to 60°-70° C. for one hour and then cooled to 0°-5° C. To the cooled solution was added 2.5 g of concentrated aqueous hydrochloric acid in 12 ml of 3A 200 proof ethanol. This mixture was kept at -5°-5° C. for one and one-half hours after which the precipitated solid was collected by filtration and washed with 50 ml of cold 3A 200 proof ethanol to yield 98.7 g (0.233 tool, 93%) of anhydrous 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride of a previously unknown crystalline modification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]([CH3:39])[C:25](=[O:38])[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])[OH:27]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]([CH:26]([OH:27])[C:25]([N:24]([CH3:23])[CH3:39])=[O:38])=[C:29]([F:37])[CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CN(C)C(=O)C(O)c1ccc(B(O)O)cc1F
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc(C(O)C(=O)N(C)C)c(F)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and {4-[2-(dimethylamino)-1-hydroxy-2-oxoethyl]-3-fluorophenyl}boronic acid. LCMS (M+H)+=519.0/521.0.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C@H:12]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]#N)[CH2:15]2)[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:22].[Na+].[CH3:24][CH2:25][OH:26]>>[C:6]1([C@H:12]([N:14]2[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]([O:26][CH2:25][CH3:24])=[O:22])[CH2:15]2)[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCO
Reactant: [OH-]
Reactant: C[C@H](c1ccccc1)N1CCC(CC#N)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C[C@H]1CCN([C@H](C)c2ccccc2)C1
Yield: 73 %

Procedure:
To a mixture of EtOH (30 mL) and H2SO4 (15 mL) at 25° C. was added (3R) 1-[(R)-1-phenylethyl]-3-(cyanomethyl)pyrrolidine 3a (7.5 g, 35 mmol) in EtOH (5 mL). The solution was heated at reflux for 7 hours, cooled, and the volume reduced by approximately one-half under reduced pressure. The residue was made basic with NaOH and extracted with EtOAc. The organic layer was dried, concentrated, and the residue distilled (bulb to bulb) to provide 4a (6.7 g, 73%); bp 120°-130° C. (0.1-0.2 mm).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH:4]([CH3:6])[CH3:5].[BH4-].[Na+]>CO>[CH2:3]([O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][CH2:1][NH2:2])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1cccc(C=O)c1OCC(C)C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CCN)c1OCC(C)C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of methylamine (64 mL of a 2.0 M solution in MeOH, 128 mmol) was added to 2-isobutoxy-3-methoxybenzaldehyde (2.45 g, 11.9 mmol) and the solution was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (64 mL) and treated with NaBH4 (0.616 g, 16.3 mmol). After stirring for 7 h, the mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (57 mL). The mixture was extracted with Et2O (3×75 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (2.43 g, 91%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.01-6.88 (m, 3H), 3.76 (s, 3H), 3.63 (t, J=6.4 Hz, 3H), 2.25 (s, 3H), 2.00-1.93 (m, 1H), 1.84 (br s, 1H), 0.98 (d, J=6.6 Hz, 6H).