Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.[O-:13][C:14]#[N:15].[K+].CC(O)C>C(O)(=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[NH:15][C:14](=[O:13])[O:1][CH:2]=2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: N#C[O-]
Reactant: O=C(CO)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)c(Cl)c2)co1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2-hydroxy-3′,4′-dichloroacetophenone (10.3 g), potassium cyanate (8.1 g) and 2-propanol (100 mL) was heated to 50° C., and acetic acid (6.0 g) was slowly added dropwise. The mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated and poured into iced water (200 mL). The precipitated solid was collected by filtration, washed with water and air-dried to give the title compound as crystals (6.0 g, 52%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 262-263° C.
Reaction SMILES: N#N.[CH:3]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:28]([O:31]C(CCl)CCl)CCl.Cl>O.ClC1C=CC=CC=1Cl>[CH:6]1[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:3]=[CH:4][C:5]=1[CH:28]=[O:31]
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=Cc1ccc2c3ccccc3c3ccccc3c2c1
Reaction time: 16 h

Procedure:
A 1 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with triphenylene (Aldrich Chemical Co., Milwaukee, WI, 53201, 30 g, 0.131 mol) and o-dichlorobenzene (150 mL). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 58 g, 0.223 mol, 26 mL), was added in one portion to the mixture. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 25.6 g, 0.223 mol, 20 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40° over 2 h and further stirred for 16 h. Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100 g) and filtered again. The solvent was removed to give a crude yellow oil which was purified by preparative HPLC using PhCH3 as the eluting solvent. The fractions containing the aldehyde were combined and the solvent removed to give an oil which solidified (8.31 g, 25%). This material was used without further purification. Recrystallization from CH2Cl2 /CH3OH gave pure 2-triphenylenecarbaldehyde mp 160°-161.5°, (C,H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>>[C:2]1([C:9]2[O:8][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: Nc1ccccc1
Product: c1ccc(-c2ccco2)cc1
Yield: 39 %

Procedure:
A solution of aniline (12.5 g, 0.134M) and i-amylnitrite (27.5 ml, 0.205M) in furan (400 ml) was stirred at 30° C. (bath temperature) for 24 hours under N2. The mixture was then washed with water and saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated. The brown residue was filtered through a short column of neutral alumina (activity grade II) using pentane as an eluent. The fractions were combined and concentrated and the residue distilled in vacuo to give pure 2-phenylfuran (7.65 g, 39% yield), bp 51°-54° C. (1.0 mm). NMR (CDCl3) δ 6.45 ppm (dd, 1H, J=1.5, 3.0 Hz, furan-H4), 6.62 (d, 1H, J=4.0 Hz, furan-H3), 7.2-7.8 (m, 6H, phenyl and furan-H5).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:18].[C:19]12([CH2:29][C:30](O)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[C:3]3=[O:18])=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
The product from Example 185A and 2-(adamantan-1-yl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (s, 1H), 7.39-7.52 (m, 5H), 2.51-2.56 (m, 2H), 2.37-2.41 (m, 2H), 2.01 (s, 2H), 1.90-1.96 (bs, 3H), 1.70-1.77 (m, 2H), 1.53-1.71 (m, 14H); MS (APCI+) M/Z 419 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1([C:11](=[O:18])[NH:12][C:13]2([C:16]#[N:17])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].[NH4+:24].[Cl-:25].N>CCO>[ClH:25].[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1([C:11](=[O:18])[NH:12][C:13]2([C:16](=[NH:24])[NH2:17])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2(C#N)CC2)CC1
Agent: CC[O-]
Agent: N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2(C(=N)N)CC2)CC1
Product: Cl
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of [1-(1-cyano-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester (250 mg, 0.942 mmol) in anhydrous EtOH (2.4 mL) was added NaOEt (21 wt % in EtOH, 0.70 mL, 1.9 mmol) via syringe in one portion. The orange reaction was stirred for 1 h. To the orange solution was added solid NH4Cl (202 mg, 3.77 mmol) and NH3 (7M in MeOH, 0.14 mL, 0.94 mmol). The reaction vial was sealed and stirred at room temperature for 15 h. The resulting suspension was filtered rinsing with EtOH. The filtrate was concentrated and the resulting solids were triturated with EtOAc to give 182 mg of [1-(1-carbamimidoyl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester hydrochloride as a white solid, m/z 283.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>ClCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ncc(OCc2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ncc(OCc2ccccc2)cn1
Yield: 96982.2 %

Procedure:
A solution of 5-(benzyloxy)pyrimidin-2-amine (60.0 g, 0.30 mmol) in dichloromethane (400 mL) was added with pyridine (30 mL, 0.37 mmol), the mixture was added dropwise with a solution of hexanoyl chloride (46 g, 0.34 mmol) in dichloromethane (100 mL) with stirring on an ice bath, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with 1 M hydrochloric acid (500 mL), and extracted with chloroform, and the organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was recrystallized from chloroform-hexane to obtain N-[5-(benzyloxy)pyrimidin-2-yl]hexanamide (87.1 g, 98%) as colorless acicular crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([Cl:20])[C:18]=1[OH:19])[C:12](OC)=[O:13]>C([O-])(=O)C.[Ca+2].C([O-])(=O)C.[Sb]=O>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][C:12]([C:11]1[CH:16]=[C:17]([Cl:20])[C:18]([OH:19])=[C:9]([Cl:8])[CH:10]=1)=[O:13])[CH2:3][O:4][C:12]([C:11]1[CH:16]=[C:17]([Cl:20])[C:18]([OH:19])=[C:9]([Cl:8])[CH:10]=1)=[O:13]
Reactant: CC(C)(CO)CO
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: CC(=O)[O-]
Agent: O=[Sb]
Agent: [Ca+2]
Product: CC(C)(COC(=O)c1cc(Cl)c(O)c(Cl)c1)COC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 200 °C
Yield: 69.5 %

Procedure:
A mechanically stirred mixture of 0.6 g of calcium acetate, 0.6 g of antimony oxide, 15.7 g (0.15 M) of 2,2-dimethyl-1,3-propanediol, and 132 g (0.6 mole) of methyl 3,5-dichloro-4-hydroxybenzoate was heated under a nitrogen atmosphere at 200° C for 18 hours. The reaction mixture was washed three times with benzene in a Waring Blendor and extracted for five days with 2 liters of hot benzene. The extract, on cooling, yielded 50.5 g of 4,4'-[2,2-dimethyl-1,3-propanediylbis(oxycarbonyl)]bis-(2,6-dichlorophenol) melting at 180°-181° C. The infrared spectrum was consistent with the indicated structure. The compound contained 4.115 meq. of OH/g, indicating a molecular weight of 486 for the bisphenol.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]3([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]([O:24]C)[C:18]=4[CH2:17][C:16]4[C:11]3=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(Cl)[Cl:27]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[ClH:27].[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]3([C:23]4[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=4[CH2:17][C:16]4[C:11]3=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: ClCCl
Reactant: COc1cccc2c1Cc1ccccc1C21CCN(CC2CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cl
Product: Oc1cccc2c1Cc1ccccc1C21CCN(CC2CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Borontribromide (2 ml.) in methylene chloride (20 ml.) is added with stirring at 0°C. to a mixture of 1'-cyclopropylmethyl-4-methoxy,9,10-dihydroanthracene-9-spiro-4'-piperidine (1.8 g.) and sodium bicarbonate (5 g.). The reaction mixture is stirred at 0°C. for 2 hours and then at room temperature for 1 hour and diluted with chloroform, more sodium bicarbonate is added, the supension is washed thoroughly with water, dried (MgSO4) and evaporated. The residue is dissolved in boiling methanol, saturated ethereal hydrogen chloride is added, and the precipitated hydrochloride is collected and recrystallised twice from methanol-ether to give 1'-cyclopropylmethyl-4-hydroxy-9,10-dihydroanthracene-9-spiro-4'-piperidine hydrochloride m.p. 290°C. (decomposition).
Reaction SMILES: [NH:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]2[N:8]=[CH:7][NH:6][C:5]=2[C:4](=[O:16])[NH:3]1.[NH2:17]N>O>[NH2:17][N:3]1[C:4](=[O:16])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1=[NH:1]
Reactant: NN
Reactant: CCCCCn1c(=N)[nH]c(=O)c2[nH]cnc21
Solvent: O
Product: CCCCCn1c(=N)n(N)c(=O)c2[nH]cnc21

Procedure:
A solution of 2-imino-3-pentyl-1,2,3,7-tetrahydro-6h-purin-6-one (750 mg, 3.39 mmol) and 18 m of hydrazine in water (30 ml) was stirred at 150° C. for 30 min on a microwave reactor. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo to yield the crude product for next step without further purification. LCMS calculated for C10H17N6O(M+H): 237.1; found: 237.2.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]2[N:21]=[C:20]([CH2:22][O:23][C:24]3[CH:41]=[CH:40][C:27]([CH2:28][N:29]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:26][CH:25]=3)[O:19][N:18]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN>>[NH3:11].[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]2[N:21]=[C:20]([CH2:22][O:23][C:24]3[CH:41]=[CH:40][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=3)[O:19][N:18]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)CC3CCCCC3)no2)cc1
Agent: CN
Product: N
Product: NCc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)CC3CCCCC3)no2)cc1

Procedure:
The title compound was prepared by a similar method to Example 11 from 2-[4-(3-[(2S)-1-cyclohexylmethylsulfonyl-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione [see Preparation 23] and methylamine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0:0 changing to 90:10:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution to afford 4-[3-((2S)-1-[cyclohexylmethylsulfonyl]-2-piperidyl)-1,2,4-oxadiazol-5-ylmethoxy]benzylamine as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[N:26]=C(C)[C:24]2[C:23](=O)CC(C3C=CC(F)=CC=3)C[C:19]=2[N:18]=1.C(OC(=O)CC)(=O)CC>>[NH2:26][C:17]1[N:18]=[C:19]([CH2:24][CH3:23])[C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][C:12]=2[N:16]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Agent: CCC(=O)OC(=O)CC
Product: CCc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)-cyclohexane-1,3-dione, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 1, 2 and 3). Propionic anhydride was used instead of acetic anhydride in stage 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](C(=O)C)=[CH:8][CH:7]=1.C(OC(=O)C)(=[O:17])C.S(=O)(=O)(O)O.[H][H]>O.C(O)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCCCc1ccc(C(C)=O)cc1
Reactant: [H][H]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=CO
Product: COCCCc1ccc(O)cc1

Procedure:
67 Grams of the p-(3-methoxypropyl)acetophenone and 620 ml of 88% formic acid (HCOOH) were mixed and stirred, after which 310 ml of acetic anhydride ((CH3CO)2O), 4 ml of concentrated sulfuric acid, and 110 ml of a 35% aqueous hydrogen perioxide solution were added thereto dropwise in that order. The resulting solution was heated to a temperature of 40° to 50° C. and then stirred for 8 hours, after which this reaction solution was poured into water. The separated oil layer was extracted, and the solvent was distilled off, after which 100 ml of CH3OH and 250 ml of a 2N aqueous sodium hydroxide solution were added to the residue, and the thus obtained solution was heated and refluxed for 2 hours. After being cooled, this reaction solution was made acid with hydrochloric acid to separate oil layer. The oil layer was extracted with benzene, and the benzene was distilled off, after which the residue was distilled under reduced pressure to obtain p-(3-methoxypropyl)phenol. The boiling point of this compound was 106°-108° C./10 mmHg. In a mixture of 100 ml of benzene and 5 ml of pyridine was dissolved 10 g of the p-(3-methoxypropyl)phenol, and 14 g of p-(3-methoxypropyl)phenyl 4-pentylcyclohexane carboxylate was added thereto dropwise, and the resulting solution was stirred at room temperature continuously for 3 hours. This reaction solution was poured into water and extracted with benzene, and the benzene was distilled off, after which the residue was recrystallized from CH3COCH3.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:12]([CH2:20][C:21](=O)[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.C(OCC)C>[NH2:4][C:3]1[C:20]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:21]([CH3:22])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#CC(N)c1ccc(F)cc1
Solvent: CCO
Solvent: CCOCC
Product: Cc1[nH]c(-c2ccc(F)cc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-(p-fluorophenyl)acetonitrile and benzoyl acetone, the open-chain intermediate compound is obtained, b.p. 120° C./0.2 mm Hg. The title compound is obtained in a 66% overall yield, m.p. 209°-210° C. (from ethanol/diethyl ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:18][C:17]=1[F:25]
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example C) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; MS (EI) 379.3 (M+OAc)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:16][C:12]=2[CH:11]=1.[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[N:16][C:12]=2[CH:11]=1
Reactant: c1coc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc2oc(-c3ccc4c(c3)nc(C3CCCO3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.5 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(furan-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 63) (90 mg, 0.234 mmol) in methanol/ethyl acetate (1:1, 6 mL) was added 10% palladium-carbon (20 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 20 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (31.4 mg, 34% yield) as a colorless amorphous mass.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:44][C:43]2([CH2:47][O:46][CH2:45]2)[CH2:42]1)([CH3:40])[CH:38]=O.N1CCCC1.Cl[Si](C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:42][C:43]5([CH2:47][O:46][CH2:45]5)[CH2:44]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CC(C)(C=O)N1CC2(COC2)C1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CC2(COC2)C1
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (222 mg, 0.46 mmol), 2-methyl-2-(6-oxa-2-azaspiro[3.3]heptan-2-yl)propanal (231.17 mg, 1.37 mmol) and pyrrolidine (0.23 mL, 2.73 mmol) in DCM (10 mL) at room temperature was added chloro(trimethyl)silane (0.17 mL, 1.37 mmol). After stirring 2 h, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by chromatography to obtain 133 mg of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-(6-oxa-2-azaspiro[3.3]heptan-2-yl)pent-2-enenitrile. MS (pos. ion) m/z: 623 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7](SC)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:30][NH2:31]>C(O)CCC>[CH2:1]([C:5]1[N:6]=[C:7]([NH:30][NH2:31])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: O
Solvent: CCCCO
Product: CCCCc1nc(NN)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A mixture of 4′-{[4-butyl-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (3.5 g), hydrazine hydrate (10 mL) and n-butanol (100 mL) was stirred at 120° C. for 6 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with methanol to give the title compound as a colorless solid (2.6 g, 77%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:34])[C:26]([N:27]3[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:35])(C)(C)C>>[Cl:34][C:25]1[C:26]([N:27]2[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28]2)=[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:20]2=[C:21]([CH:24]=1)[C:22](=[O:23])[N:13]([OH:12])[C:14]3=[O:35]
Reactant: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(OC(C)(C)C)C3=O)C1
Solvent: O=C(O)C(F)(F)F
Product: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure from Example 62, TFA (1.0 mL) and 2-tert-butyloxy-5-chloro-6-[3-methoxypyrrolidin-1-yl]-benzo[de]isoquinoline-1,3-dione (0.2 g, 0.5 mmol, from Example S2) was stirred at room temperature overnight, concentrated, and the solid recrystallized from ethanol/ether solution to give 0.02 of the title compound, mp 136-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][I:32])=[CH:29][CH:28]=1>C(Cl)Cl>[I-:32].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N+:8]2[CH:9]=[CH:10][N:6]([CH2:5][CH:4]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:3]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])[CH:7]=2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: Clc1ccc(CI)cc1
Solvent: ClCCl
Product: Clc1ccc(C[n+]2ccn(CC(OCc3ccc(Cl)cc3Cl)c3ccc(Cl)cc3Cl)c2)cc1
Product: [I-]

Procedure:
4.2 Parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)-phenethyl]imidazole, 3.7 parts of p-chlorobenzyl iodide and 56 parts of methylene chloride are mixed together and stirred at reflux temperature for five hours to obtain a 1-(p-chlorobenzyl)-3-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazolium iodide product which remains in the reaction mixture. The reaction mixture is warmed to evaporate off the solvent and to recover the product as residue. The crude product is purified by washing with 2-propanol and crystallizing from a mixture of 4-methyl-2-pentanone and diisopropyl ether, to yield 1-(p-chlorobenzyl)-3-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazolium iodide; m.p. 145° -148° C.