Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10](N)=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[N:4][C:2]1=S>C(O)CC.[Ni]>[N:1]1[CH:10]=[C:9]2[C:5](=[N:6][CH:7]=[N:8]2)[NH:4][CH:2]=1
Reactant: Nc1[nH]c(=S)nc2nc[nH]c12
Agent: [Ni]
Solvent: CCCO
Product: c1nc2cnc[nH]c-2n1
Yield: 140.8 %

Procedure:
4.39 g (11 mmoles) of thioisoguanine and 7.10 g (121 mmoles) of neutral Raney-nickel are refluxed in 50 ml of 1-propanol for 4.5 hours. The nickel was filtered off and the filtrate evaporated to dryness. The residue (3.79 g/93.8%) was dissolved in 20 ml of chloroform and 0.4 ml methanol and filtered through 24 g of silicagel in a column also with 2% methanol. The combined fractions were washed with 1N NaOH and the organic phase evaporated to dryness. The residue (2.69 g/66.6%) was dissolved in 30 ml of dichloromethane and 0.6 ml methanol and again filtered through 30 g of silicagel. A total of 1.86 g (46.0%) of 3H-purine was isolated, which was dissolved in 20 ml of methanol, treated with 5.4 ml of 1N methanolic HCl, and evaporated in vacuo to dryness. Crystallization and recrystallization from dichloromethane and ethyl acetate gave 1.75 g (39.4%) of 3H-purine hydrochloride with mp 170-85° C.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=[S:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([F:29])=[C:21]([CH:28]=1)[CH:22]=[N+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.BrC1C=CC(F)=C(C=1)C=O.N1CCCC1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([F:29])=[C:21]([CH:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]2[N:1]([C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([NH2:10])=[S:9])[CH:2]=[CH:3][CH:4]=2)[CH:28]=1
Reactant: NC(=S)c1ccccc1-n1cccc1
Reactant: Fc1ccc(Br)cc1C=[N+]1CCCC1
Agent: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Solvent: C1CCNC1
Product: NC(=S)c1ccccc1-n1cccc1C(c1cc(Br)ccc1F)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-thiobenzamide and 1-(5-bromo-2-fluoro-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 5-bromo-2-fluorobenzaldehyde and pyrrolidine.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1)=[O:10].O>CS(C)=O>[O:10]1[CH2:2][CH:9]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(C2CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Trimethylsulfoxonium iodide (1.65 g, 7.5 mmol) was added in two portions to a solution of NaH (300 mg, 7.5 mmol) in anhydrous DMSO (10 mL) at room temperature. The resulting mixture was stirred for 1 hour, whereupon a solution of phenylmethyl 4-formyl-1-piperidinecarboxylate (1.24 g, 5.0 mmol) in anhydrous DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, then poured into cold water (100 mL), and extracted with Et2O (2×100 mL). The extracts were combined, washed with water, brine, and dried (Na2SO4). The solvent was removed in vacuo to give the title compound (0.95 g, 73%) as a colorless oil. MS (ES) m/e 262 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](Cl)[C:6]=2[C:13]#[N:14].[NH3:15]>CO>[NH2:15][C:7]1[C:6]([C:13]#[N:14])=[C:5]2[C:10]([CH:11]=[C:2]([Cl:1])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Reactant: N
Solvent: CO
Product: N#Cc1c(N)ccc2cc(Cl)cnc12
Yield: 53 %

Procedure:
110 g of 3,7-dichloro-8-cyanoquinoline, 500 ml of methanol and 500 ml of liquid ammonia were heated at 150° C. for 10 hours in an autoclave. The pressure was let down, after which the discharged mixture was filtered under suction, and the solid was recrystallized from methylglycol, in the presence of active charcoal. 54 g of 7-amino-3-chloro-8-cyanoquinoline of melting point 246° C. were obtained. Yield: 53% of theory.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46].C(N(CC)CC)C>ClCCl>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH:51][C:26]([C:25]1[CH:24]=[N:23][C:22]([NH:21][C@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)=[N:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:30][CH:29]=1)=[O:28])[CH3:46]
Reactant: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-{(S)-3-Methyl-1-[2(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-nicotinic acid (31.1 g wet with ethyl acetate, theoretical 65.8 mmol) was dissolved in dichloromethane (270 mL). 1-Hydroxybenotriazole hydrate (15.1 g, 98.7 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18.9 g, 98.7 mmol). beta-Alanine ethyl ester hydrochloride (12.1 g, 79.0 mmol) was added and the reaction was placed in an ice bath. When only slightly cool, triethylamine (18.3 mL, 132 mmol) was added over 3 min. The bath was then removed and the reaction was stirred at room temperature as a solution. At 16 h, most of the dichloromethane was rotovapped off. The residue was partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with additional ethyl acetate and the combined organics were washed with sat. NaHCO3 two times. The first aqueous was back extracted with ethyl acetate to remove a small amount of product. The combined organics were washed with brine and dried over MgSO4. The material was purified by silica gel flash chromatography (ethyl acetate/heptane) and then further purified by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21 mm×250 mm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 65 mL/min. The purified material was taken up in ethyl acetate, filtered through a course frit and concentrated in vacuo to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester with ethyl acetate (29.2 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.83 (s, 2H) 8.54 (d, J=8.0 Hz, 2H) 8.46 (d, J=2.0 Hz, 1H) 7.81 (dd, J=8.7, 2.2 Hz, 1H) 7.73 (d, J=8.4 Hz, 2H) 6.64 (t, J=5.8 Hz, 1H) 6.36 (d, J=8.6 Hz, 1H) 5.13 (d, J=6.7 Hz, 1H) 4.97-5.08 (m, 1H) 4.09-4.21 (m, 2H) 3.68 (q, J=5.9 Hz, 2H) 2.60 (t, J=5.9 Hz, 2H) 1.81-1.95 (m, 1H) 1.67-1.81 (m, 2H) 1.26 (t, J=7.1 Hz, 3H) 1.03 (d, J=6.1 Hz, 3H) 1.00 (d, J=6.1 Hz, 3H); MS (M+1): 530.2. Analytical chiral SFC: Column—Chiralcel OJ-H. Dimensions: 4.6 mm×25 cm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 2.5 mL/min. Retention time: 5.18 minutes.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[O:10][C:11]([CH3:18])=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=2)[CH:25]=1>ClCCl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][S:14]([C:13]3[CH:12]=[C:11]([CH3:18])[O:10][C:9]=3[CH3:8])(=[O:16])=[O:15])[CH3:33])=[CH:28][CH:27]=2)[CH:25]=1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
Triethylamine (41.1 μl, 0.295 mmol) then 2,5-dimethyl-3-furansulfonyl chloride (19.1 mg, 0.0982 mmol) were added to a solution of 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl) and the organic phase separated, dried over anhydrous magnesium sulfate and the solvent evaporated. The crude product was purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (3.9 mg, 0.0097 mmol, 11.8%). 1H NMR (400 MHz, CDCl3): δ 7.40, 7.23 (a/b, 4H), 7.05-6.88 (m, 3H), 5.99 (s, 1H), 4.67 (m, 1H), 4.55 (m, 1H), 3.78 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 426 [M+Na]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[S:6][CH:7]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+]>CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]2=[O:17])[S:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1csc(-n2c(=O)[nH]c3ccccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 1-[4-(methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one from Step B (710 mg, 2.67 mmol) and tert-butyl bromoacetate (578 mg, 2.97 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (194 mg of a 60% dispersion in mineral oil, 4.85 mmol). The mixture was stirred at 0° C. for 15 min, then quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×35 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:15]1(=[N:2][NH:1][C:3]2[N:8]=[N:7][C:6]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=3[CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: NNc1cc2c(nn1)CCCCCC2
Product: c1c(NN=C2CCCCC2)nnc2c1CCCCCC2

Procedure:
A solution of 10.0 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 100 cc of cyclohexanone is boiled at reflux at a bath temperature of 180° for 1 hour and 45 minutes. The mixture is concentrated in a vacuum, whereby the crystalline title compound is obtained and is recrystallized from isopropanol. M.P. 160°-162° (decomp.).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].C(OC(NCC1C=CC=CC=1CC(O)=O)=O)(C)(C)C.[ClH:36].Cl.[CH3:38][NH:39][C@@H:40]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:41][N:42]1[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43]1.CN[C@@H](C1C=CC=CC=1)CN1CCCC1.C(N(C(C)C)CC)(C)C.Cl>ClCCl.CCOCC>[ClH:36].[OH:47][C@H:44]1[CH2:45][CH2:46][N:42]([CH2:41][C@@H:40]([N:39]([CH3:38])[C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:12][CH:11]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:43]1
Reactant: CN[C@H](CN1CC[C@H](O)C1)c1ccccc1
Reactant: CS(=O)(=O)NCc1ccc(CC(=O)O)cc1
Agent: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Agent: CN[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CN(C(=O)Cc1ccc(CNS(C)(=O)=O)cc1)[C@H](CN1CC[C@H](O)C1)c1ccccc1

Procedure:
Compound 13a was prepared by following the procedure of Example 1, Step f, except 12a was substituted for 6a, 1-[2-methylamino-2-(S)-phenyl-ethyl]-pyrrolidin-3-(S)-ol dihydrochloride was substituted for methyl-[1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl]-amine and diisopropylethylamine (3.3 eq) was substituted for diisopropylethylamine (2.2 eq). The resulting oil was dissolved in dichloromethane (0.1 M) and a solution of hydrochloric acid (5.5 eq) in ether (2.0 M) was added slowly at 0° C. The solvent was removed under reduced pressure. The resulting solid was triturated with ether then filtered off to afford the product as the hydrochloric acid salt. (55%) 1H NMR (400 MHz, DMSO-d6) δ 10.22-10.72 (m, 1H), 7.55 (m, 1H), 7.18-7.42 (m, 9H), 6.17 (m, 1H), 5.42-5.62 (m, 1H), 4.44 (m, 1H), 4.13 (m, 3H), 3.84 (m, 2H), 3.40-3.72 (m, 3H), 3.17 (m, 1H), 2.83 (s, 3H), 2.76 (m, 3H), 2.09-2.35 (m, 1H), 1.89 (m, 1H). Mass Spectral Analysis m/z=446.4 (M+H)+ tR=3.45 min (98%)
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1)[CH3:2].[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29].N[CH:32](O)C(C)C>C1COCC1.CN1C(=O)CCC1>[CH2:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([NH:26][CH2:27][C:28]([OH:30])([CH3:32])[CH3:29])[N:4]=1)[CH3:2]
Reactant: CCc1nc(SC)ncc1-c1ccnc(Nc2ccc(C#N)cc2)n1
Reactant: CC(C)C(N)O
Reactant: CC(O)CN
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1nc(NCC(C)(C)O)ncc1-c1ccnc(Nc2ccc(C#N)cc2)n1
Yield: 9.5 %

Procedure:
4-(4′-Ethyl-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (36a) (48.6 mg, 0.112 mmol) and 1-amino-2-propanol (29.8 mg, 0.335 mmol) were dissolved in THF (540 μl) and NMP (54.0 μl), then the reaction mixture was microwaved at 150° C. for 1 hour. Additional 1-amino-2-methylpropanol (99.8 mg, 1.12 mmol) was added, and the reaction mixture was microwaved further at 150° C. an additional 1 hour. Additional 1-amino-2-methylpropanol (99.8 mg, 1.12 mmol) was added, and the reaction mixture was microwaved further at 200° C. The crude reaction mixture was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes using 0.1% TFA modifier] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM] to obtain the desired product as a pale yellow solid (4.14 mg, 9% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.20-1.27 (m, 9 H) 2.94 (q, J=7.58 Hz, 2 H) 3.51 (s, 2 H) 4.55 (s, 1 H) 7.04 (d, J=5.56 Hz, 1 H) 7.62 (m, J=9.09 Hz, 2 H) 7.96 (m, J=8.59 Hz, 2 H) 8.44 (s, 1 H) 8.52 (d, J=5.05 Hz, 1 H). HRMS (ES+) for C21H23N7O.H+ [MH+]: calcd, 390.2042. found, 390.2023. UV-LC: 96.40/95.08% UV purity at 214/254 nm; tR=5.31 minutes over 7.75 minutes.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=O.[CH2:5]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.C1CCN2C(=NCCC2)CC1>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:4][CH2:3][CH2:1][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: C=CC=O
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc(CNCCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A solution of acrolein (90%, 3.2 g, 57 mmol) in THF (2 ml) was dropwise added to a solution of 4-benzylpiperidine (10.0 g, 57 mmol) and DBU (85 μl, 0.57 mmol) in THF (10 ml) for 10 minutes at −20° C. under stirring. The mixture was stirred for an hour raising the temperature from −20° C. to −10° C. Benzylamine (6.1 g, 57 mmol) and triacetoxy sodium borohydride (24.2 g, 114 mmol) were added to the reaction mixture successively at −10° C., and the mixture was stirred for 19 hours raising the temperature to room temperature. An aqueous solution of 2N sodium hydroxide (100 ml) was added to the reaction mixture under ice cooling and the mixture was stirred for 30 minutes, and extracted with diethyl ether (100 ml, 80 ml×2). The organic phase was dried over magnesium sulfate (anhydrous), then concentrated under reduced pressure. The residue was dissolved in 2-propanol (50 ml) and to the solution was added a solution of 4N hydrogen chloride in ethyl acetate (50 ml) with stirring. The resulting precipitate was collected by filtration. The precipitate was washed with 2-propanol (20 ml×3) and dried under reduced pressure to give the title compound as a white crystal (6.5 g).
Reaction SMILES: [CH:1]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:11]=34)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:45]([C:48]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCCC3COC4)N=2)=CC=1)=[C:46]=[O:47]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:5]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH:20][C:46]([NH:45][CH3:48])=[O:47])=[CH:21][CH:22]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:29])([F:28])[F:30])[N:24]=[CH:25][C:11]=34)[CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: O=C=Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of 4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (50 mg, 0.12 mmol) in dichloromethane (3 mL) was treated triethylamine (160 μL), followed by triphosgene (27 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.2 mL)—was added to the 9-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 476.3 (M+H)+
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23](=[O:33])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:20]2)[C:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])([OH:34])[CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:16]1([OH:34])[CH2:15][CH:14]([CH2:13][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][CH:21]2[CH:17]1[CH2:18][N:19]([C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[CH2:20]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1CC(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
3.05 g of p-toluenesulphonyl chloride are added to a solution of 3.4 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol and 2.24 cm3 of triethylamine in 150 cm3 of dichloromethane. The mixture is stirred at 20° C. for 20 hours, washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 4.1 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:33])=[C:26]([F:32])[CH:27]=2)=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(C(=O)OC(C)C)c(CN(C)C2CC2)c1
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1F

Procedure:
Following General Procedure B and using 2-[(cyclopropyl-methyl-amino)methyl]-4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.05 g, 0.18 mmol), 2-fluoro-4-iodo phenylacetic acid methyl ester (0.07 g, 0.24 mmol), triethyl amine (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 15-16% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.04 g, 50%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C@H:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[CH:11]=[N:12][CH:13]=2)[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH:18]1[CH2:19][CH2:20][C@H:16](/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](/C=C/c2cncc(OC3CCOCC3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C/[C@H]1CCNC1)\c1cncc(OC2CCOCC2)c1
Yield: 60.6 %

Procedure:
A solution of tert-butyl (R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (18 g, 48.13 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (40 mL) was stirred at ambient temperature for 2 h. The reaction was concentrated on a rotary evaporator, and the residue was partitioned between saturated sodium chloride (50 mL) and chloroform (100 mL). The mixture was basified to pH 9 with 10% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer extracted with chloroform (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator to give (R)-3-((E)-2-(pyrrolidin-3-yl)vinyl)-5-(tetrahydro-2H-pyran-4-yloxy)pyridine (8.0 g) as a gum. This was dissolved in methanol (100 mL) and galactaric acid (3.0 g, 14.6 mmol) was added and the mixture was heated to reflux. This hot solution was filtered, and filtrate was allowed to cool to ambient temperature. The crystallized product was filtered and solid was suspended in 10% water in ethanol (180 mL). The suspension was heated to reflux and hot solution was filtered. The filtrate was allowed to cool to ambient temperature. Crystallized product was filtered and dried on high vacuum pump to give (R)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydro-2H-pyran-4-yloxy)pyridine hemigalactarate (4.5 g). MP: 179° C. 1H-NMR (CD3OD, 300 MHz): δ 8.04 (s, 1 H), 8.01 (d, J=2.2 Hz, 1 H), 7.36 (s, 1 H), 6.46 (d, J=16.0 Hz, 1 H), 6.21 (dd, J=16.0, 7.5 Hz, 1 H), 4.65-4.4.54 (m, 1 H), 4.12 (s, 1 H), 3.89-3.83 (m, 2 H), 4.80 (s, 1 H), 3.56-3.33 (m, 4 H), 3.27-3.18 (m, 1 H), 3.12-2.96 (m, 2 H), 2.23-2.14 (m, 1 H), 1.98-1.91 (m, 2 H), 1.88-1.78 (m, 1 H), 1.68-1.58 (m, 2 H); MS (m/z): 275 (M+1).