Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][C:14](I)=[N:15][C:16]=3[C:7]=2[N:6]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[N:5]=1)(=[O:3])[NH2:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([C:4]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([C:34]4[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])=[N:15][C:16]=3[C:7]=2[N:6]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(N)=O)c3c2-c2nc(I)ncc2CC3)CC1
Reactant: OB(O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(N)=O)c3c2-c2nc(-c4c(F)cccc4F)ncc2CC3)CC1
Yield: 105.9 %

Procedure:
To a solution of tert-butyl 4-[(3-carbamoyl-8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-1-yl)methyl]piperidine-1-carboxylate (30 mg, 0.036 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, 17.6 mg (0.11 mmol) of 2,6-difluorophenylboronic acid 13.7 mg (0.017 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium complex with dichloromethane and 54 mg (0.167 mmol) of cesium carbonate, were successively added. The mixture was submitted to microwave irradiation at 80° for 1 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash chromatography on silica gel column (DCM/EtOAc 7/3), 20 mg (70%) of tert-butyl 4-{[3-carbamoyl-8-(2,6-difluorophenyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidine-1-carboxylate were obtained. The product was dissolved in DCM (2 ml) and 4M HCl in 1,4-dioxane (2 ml) was added. The reaction was stirred at room temperature for 1 hour, the solvent was evaporated to dryness. The solid was treated with ethyl ether and the precipitate collected by filtration to give the title compound as a pale yellow solid 17 mg (85%). LC/MS (254 nm) HPLC method 2 Rt 4.14 min. 1H NMR (401 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.57 (d, J=9.76 Hz, 1H), 8.30 (d, J=10.01 Hz, 1H), 7.55-7.69 (m, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 7.23-7.33 (m, 2H), 4.57-4.66 (m, 2H), 3.16-3.26 (m, 2H), 3.01-3.14 (m, 4H), 2.69-2.85 (m, J=10.74 Hz, 2H), 2.09-2.29 (m, J=7.20 Hz, 1H), 1.56-1.70 (m, J=12.94 Hz, 2H), 1.32-1.48 (m, 2H) HRMS (ESI) calcd for C21H27IN6O3 [M+H]+ 425.1896 found 425.1896
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:19][CH2:18]1>>[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][N:3]=[C:2]2[NH:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:21][CH2:22]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1cc(OC)c2cnnc(Cl)c2c1
Product: COc1cc(OC)c2cnnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 2.4 by reacting 1-chloro-5,7-dimethoxyphthalazine described in 13.2 with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:22]2[CH2:24][CH2:23]2)[C:11](N2[C@@H](C(C)C)COC2=O)=[O:12])=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][C:27]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C)C=O.O>[CH:22]1([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][O:12][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)[CH2:23][CH2:24]1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1

Procedure:
Under a nitrogen atmosphere a suspension of 0.06 gram (0.0024 mole) of 97% sodium hydride in 2.2 mL of dimethylformamide was stirred, and a solution of 0.40 gram (0.002 mole) of stereoisomer (A) of 2-cyclopropyl-2-(4-chlorophenyl)ethyl ethanol in 1.0 mL of dimethylformamide was slowly added. Upon completion of addition, the reaction mixture was stirred for 1.5 hours, and then a solution of 0.46 gram (0.0019 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 1.0 mL of dimethylformamide was added. Upon completion of addition, the reaction mixture was stirred for one hour, and then 2-3 mL of water was added. The mixture was poured into 75 mL of aqueous, 10% hydrochloric acid and then was extracted with two 50 mL portions of hexane. The combined hexane layers were washed with 25 mL of a saturated, aqueous solution of sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to rotating disk thin layer chromatography on silica gel using diethyl ether: hexane (19:1) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.55 gram of stereoisomer (A) of (4-fluoro-3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether as an oil. The nmr spectrum was consistent with the proposed structure. [α]D25 =(+)22.19°.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([Sn](CCCC)(CCCC)CC=C)[CH2:20][CH2:21]C>C(#N)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH2:21][CH:20]=[CH2:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: C=CCc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C

Procedure:
A 9 g portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 11.1 g of tri-n-butyl-2-propenylstannane and 1.69 g of tetrakis(triphenylphosphene) palladium in 40 mL of acetonitrile in a sealable tube. Argon was bubbled through the mixture, the cap replaced, and the reaction heated at 90° for 18 h. Upon cooling, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was triturated with diethyl ether to obtain 4.23 g of crystalline product, and a second crop of 1.31 g of product was also obtained. mp 144°-146°. FDMS 255 M+. Calcd for C17H21N1O2 :
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[NH:12]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[N:13]1>C(O)C.[Zn]>[NH:12]1[CH:16]=[C:15]([CH:17]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7])[CH:14]=[N:13]1
Reactant: O=Cc1cn[nH]c1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1cn[nH]c1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (546.0 mg, 5.29 mmol) and zinc (515.5 mg, 7.89 mmol) in ethanol (3.0 ml) was added acetic acid (950.0 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 45 minutes. After cooling the mixture to 5° C. again, pyrazole-4-carbaldehyde (255.4 mg, 2.66 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:29]([Si:35]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])Cl)([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[C:1]([O:5][Si:35]([C:29]([CH:32]([CH3:34])[CH3:33])([CH3:31])[CH3:30])([CH:40]([CH3:41])[CH3:42])[CH:37]([CH3:38])[CH3:39])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CC(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 14.4 g (0.2 mol) of acrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 47.0 g (0.20 mol) of thexyldiisopropylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 38.6 g of a fraction having a boiling point of 87-92° C./0.13 kPa.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.[S:17]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:22][C:19]2[CH:20]=[CH:21][S:17][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2
Reactant: OCc1ccsc1
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccsc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 500 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 24 ml of toluene, and 0.39 ml of 3-thienylmethanol and 1.00 g of cynomethylene tri-N-butylphospholan were added at room temperature, followed by overnight stirring at 110° C. A 0.39 ml portion of 3-thienylmethanol and 1.00 g of cyanomethylene tri-N-butylphospholan were added to the reaction liquid, followed by stirring at 110° C. for 8 hours. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20 to 1:10) to obtain 378 mg of ethyl 2,3-dimethyl-1-(3-thienylmethyl)-1H-indole-5-carboxylate as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)cccc2n1
Yield: 53 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-chlorobenzoyl chloride (71.8 mg; 0.41 mmol) to obtain 40.4 mg. (53% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.53 (m, 4H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (br s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 5.92 (br s, 2H), 4.56 (br s, 1H), 3.64 (m, 1H), 3.09 (m, 4H), 2.77 (m, 2H) ESIMS+384.1 m/z
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.C([O:17][C:18](=[O:20])C)C(C)C.[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].Cl>O1CCCC1>[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][C:5]([CH3:6])([CH3:7])[C:18]([OH:20])=[O:17])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CC(C)NC(C)C
Reactant: CC(=O)OCC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (3.08 ml) was dissolved in tetrahydrofuran (40 ml) and to the mixture was added n-butyl lithium (13.8 ml; 1.6M in hexane) at −78° C. and then was added isobutylacetate (0.93 ml) and the mixture was stirred for 1 hour at 30° C. To the reaction mixture was added a solution of 4-isopropylbenzyl chloride (2.19 g) in tetrahydrofuran (10 ml) at −78° C. and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into cool hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (1.73 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)c1cccn1C
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=Nc1ccc(OC)cc1)c1cccn1C
Yield: 58 %

Procedure:
To a solution of 4.0 g ethyl 1-methylpyrrole-2-glyoxylate and 2.96 g p-anisidine in 20 ml toluene is added 24 mg p-toluenesulfonic acid. Heating at reflux for 4 days with water being removed with a Dean-Stark trap is followed by washing successively with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. After drying, evaporation of the solvent affords a dark solid. Recrystallization from isopropanol gives a 58% yield of ethyl α-(4-methoxyphenylimino)-1-methylpyrrole-2-acetate, m.p. 83°-85° C.
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([O:11][CH3:12])[CH:5]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1>[F:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: ClCCNCCCl
Reactant: COc1cc(F)ccc1N
Agent: Cl
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc(F)ccc1N1CCNCC1
Temperature: 20 °C
Yield: 25 %

Procedure:
9 ml of chlorobenzene and H2O were distilled from a solution of 1.14 g of p-TosOH (6.03×10−3 moles) in 200 ml of chlorobenzene. The solution was cooled to 20° C. and then 1.19 g of 4-fluor-2-methoxyaniline hydrochloride (6.7×10−3 moles) and 1.31 g of bis (2-chloroethyl)amine hydrochloride (7.36×10−3 moles) were added. The reaction was held under reflux for 72 hours after which the solvent was removed and the residue was extracted with 5 ml of NaOH 2N and 30 ml of toluene. The organic phase was washed with H2O, was dried with Na2SO4 and the toluene was removed. The product was purified by silica column using dichloromethane/MeOH (9:1) as mobile phase. An oil was obtained. Yield: 25%.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.O=[C:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].CO>[CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: O=C1CCOCC1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C4CCOCC4)CC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (44.0 mg, 0.105 mmol), 4-oxotetrahydropyran (37.7 mg, 0.366 mmol) and sodium triacetoxyborohydride (100 mg, 0.471 mmol) in 1,2-dichloroethane (1.0 mL) was stirred at room temperature over the weekend. The reaction was diluted with saturated NaHCO3 (aq) and methanol. The mixture was concentrated to dryness and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((3-methyl-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.34 (26 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:27]([NH2:26])=[O:28])[CH2:21][CH2:22]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Yield: 47.2 %

Procedure:
A mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 5.1 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized from ethyl acetate (2×) to yield 2.7 g (47%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 148°-150°.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].[Li+].[OH-].Cl>C1COCC1.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[C:5]([O:11][CH3:12])[CH:6]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)ccc1C(=O)O
Yield: 72.2 %

Procedure:
To a solution of 4-amino-2-methoxy benzoic acid methyl ester (5 g; 27 mmol) in THF/H2O (125 mL/25 mL) was added LiOH (4.8 g; 200 mmol) and the slurry was refluxed for 3.5 hours. The reaction mixture was neutralized using 4 M HCl (aq) and the resulting precipitate isolated by filtration and washed with H2O (2×15 mL) to give 3.26 g (80%) of an off-white solid. Mp. 144-146° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccccc1CBr
Reactant: OCCc1cccc(O)c1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1cccc(CCO)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
3-(2-Hydroxyethyl)phenol (1.0 g, 7.24 mmol) and methyl 2-(bromomethyl)benzoate (1.74 g, 7.6 mmol) was dissolved in acetonitrile (10 ml). Potassium carbonate anhydrous (2.0 g, 14.48 mmol) was added. After stirring at 60° C. for three hours PS-trisamine was added (0.3 eq) and was stirred overnight. The PS-trisamine was filtered off and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic layer was washed with 3 portions of water (3×10 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 1.99 g of methyl 2-{[3-(2-hydroxyethyl)phenoxy]methyl}benzoate (yield 90%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:19])[CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH:14]([CH3:15])[CH2:13][NH:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].CC(C)=O.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][CH:14]([CH3:15])[C:10]([CH2:9][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:19])([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1CNCC1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 0.5 °C
Yield: 95.1 %

Procedure:
A 2 N aqueous sodium hydroxide solution (20.2 ml) was added to a mixture of (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Reference Example 1a (9.84 g, 40.5 mmol), acetone (39 ml) and water (49 ml) with stirring under ice-cooling (0 to 1° C.), and the reaction mixture was dissolved by stirring for 45 minutes. Benzyl chloroformate (6.35 ml, 44.5 mmol) and a 2 N aqueous sodium hydroxide solution (22.3 ml) were simultaneously added dropwise to the reaction mixture at an internal temperature of 3.5° C. or lower with stirring under ice-cooling (0 to 1° C.) over 20 minutes. The reaction liquid was stirred in an ice bath and gradually returned to mom temperature. This was stirred at mom temperature overnight. A 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction liquid with stirring under ice-cooling (internal temperature: about 15° C.), and the mixture was adjusted to pH 12. This reaction liquid was returned to room temperature and washed three times by adding ethyl ether. The aqueous layer was adjusted to pH 2 to 3 by sequentially adding a 2 N aqueous hydrochloric acid solution (20.2 ml) and a 1N aqueous hydrochloric acid solution (13 ml) with stirring under ice-cooling (internal temperature: 5° C. or lower). The aqueous layer was returned to mom temperature and extracted with ethyl acetate three times. The organic layer was washed with brine, and then dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water four times and then with brine, dried over sodium sulfate, filtered and concentrated to give the title compound (14.53 g, yield: 95.1%).
Reaction SMILES: Cl[C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.CN.[CH:28]([N:31](CC)C(C)C)(C)C>C1COCC1>[CH3:28][NH:31][C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring solution of 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (36 mg, 0.09 mmol) in 1 mL THF was added methylamine (2 M in THF, 0.13 mL, 0.26 mmol), followed by N,N-diisopropylethylamine (12 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The resulting crude title compound was used in the next step without further purification. HPLC/MS: retention time=4.06 min, [M+H]30 =386.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[ClH:36]>O.C(#N)C>[ClH:36].[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrCCCCCCN1CCCCCC1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC#N
Product: O=C1Nc2ccccc2N(CCCCCCN2CCCCCC2)c2ccccc21
Yield: 15 %

Procedure:
Prepared analogously to Example 6 from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, n-butyl-lithium and 1-bromo-6-(hexahydro-1H-1-azepinyl)hexane in a yield of 15% of theory. The monohydrochloride, which is sparingly soluble in water, melted at 103°-105° C. (from acetonitrile using activated charcoal).