Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([F:23])[C:17]=2[C:24]#[N:25])=[N:9]S(C(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[C:16]3[C:17](=[C:18]([F:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)[C:24]([NH2:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cc(Cl)cc(F)c1C#N
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cc(Cl)cc32)ccn1
Yield: 83 %

Procedure:
The title compound was synthesized as described for Example 11i in 83% yield, starting from N-((3-bromophenyl)(5-chloro-2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (2 g, 4.53 mmol) and 4-bromo-2-methylpyridine (0.935 g, 5.43 mmol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34].C(N(CC)C(C)C)(C)C.ClCCl>C(#N)C.CO>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (1.0 g, 2.2 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.72 g, 2.2 mmol), and N,N-diisopropylethylamine (0.75 mL, 4.4 mmol) in acetonitrile (70 mL). Heat to reflux. After 72 hours, cool and pour the reaction mixture into dichloromethane (700 mL). Extract twice with water and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 25% methanol/0.6% concentrated aqueous ammonia/ethyl acetate to give the title compound: Rf=0.38 (silica gel, 25% methanol/0.6% concentrated aqueous ammonia/ethyl acetate).
Reaction SMILES: C1(C(=O)C(SC)=CC=C(N(C)C)C(OCC)=O)C=CC=CC=1.F[B-](F)(F)F.[CH3:28][N:29]([CH3:41])[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:32]=[N+](C)C.CC[O-].[Na+].[C:46]([C:54]1[CH:55]=[C:56]([CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH:57]=[CH:58][CH:59]=1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(O)C>[CH3:28][N:29]([CH3:41])[C:30](=[CH:31][CH:32]=[C:60]([C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([C:46](=[O:53])[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:55]=1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1
Agent: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)c1cccc(C(=O)c2ccccc2)c1
Yield: 53.4 %

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (17.8 g), a 2M ethanolic solution of sodium ethylate (31.3 cc) and ethyl (3-benzoylphenyl)acetate (16.8 g) in ethanol (100 cc). After purification by chromatography on a silica column with dichloromethane as eluent, diethyl 2-dimethylamino-5-(3-benzoylphenyl)-2,4-hexadienedioate (14 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: Br[C@@H:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21]([O-:24])(=[O:23])C.[K+].CN(C)C=O>O>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C@H:3]([CH3:2])[C:21]([OH:24])=[O:23])[CH:13]=[CH:12]2
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cc(C(OC)(OC)[C@H](C)Br)ccc2c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 97 %

Procedure:
A mixture of (+)(S)2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), N,N-dimethylformamide (14 ml) and of water (8 ml) is heated at 100° C. under stirring. The reaction mixture is worked up as described in example 1 to provide (+)(S)2-(6-methoxy-2-naphthyl)-propionic acid (2.23 g; 9.7 mmol; yield 97%), m.p. 155°-157° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][C:17](=[O:32])[C:18]([F:31])([F:30])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([F:29])=[CH:21][CH:20]=2)[C:8]=1[F:33])(=[O:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([F:33])=[C:9]([NH:16][C:17](=[O:32])[C:18]([F:30])([F:31])[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([F:29])=[CH:21][CH:20]=2)[CH:10]=[CH:11][C:12]=1[NH2:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)OCCc1c(N)ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 5 h
Yield: 83.3 %

Procedure:
A mixture of 2-{3-[2,2-difluoro-2-(4-fluoronaphthyl)acetylamino]-2-fluoro-6-nitrophenyl}ethyl acetate (4.9 g, 10.5 mmol), as prepared in the preceding step, and Pd/C (10%, 500 mg) in ethanol (50 mL) and THF (50 mL) was stirred under hydrogen for 5 hours. The reaction mixture was filtered through Celite, and washed with THF and MeOH. The filtrate and washings were combined, concentrated in vacuo, and flash chromatographed on silica gel eluting with EtOAc/DCM (0 to 2%) to produce the title compound (3.8 g, 83%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.10 (s, 1H), 7.82 (m, 2H), 7.63 (m, 2H), 7.19 (t, J=8.6 Hz, 1H), 6.46 (d, J=8.7 Hz, 1H), 4.19 (t, J=7.4 Hz, 2H), 4.08 (s, 2H), 2.91 (t, J=7.3 Hz, 2H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:20](O)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH:14]=[C:13]([O:18][CH2:20][CH3:21])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)CC(=O)C2)cc1OC
Reactant: CCO
Agent: Cl
Product: CCOC1=CC(=O)CC(c2ccc(OC)c(OC)c2)C1
Yield: 29.1 %

Procedure:
5-(3,4-Dimethoxyphenyl)cyclohexan-1,3-dione (31.8 g) was suspended in ethanol (500 ml), and concentrated hydrochloric acid (20 ml) was added prior to reflux for 3 hours. After the reaction solvent was concentrated under reduced pressure, it was dissolved in chloroform and washed with saturated sodium bicarbonate water. After drying with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure producing crude crystals which were then washed with diethyl ether to give 10.3 g of 5-(3,4-dimethoxyphenyl)-3-ethoxy-2-cyclohexen-1-one (29.1%).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][CH2:5][CH:4]1[OH:15].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[Cl-].[NH4+]>CN(C=O)C>[C:23]([Si:20]([CH3:22])([CH3:21])[O:19][CH2:18][CH2:17][O:15][CH:4]1[CH2:3][O:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][CH2:5]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: OC1COC(c2ccccc2)OC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOC1COC(c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Sodium hydride (133 mg, 3.32 mmol) was added to 5 mL of a solution of cis-1,3-O-benzylideneglycerol (300 mg, 1.66 mmol) in DMF, and the mixture was stirred at room temperature for two hours. (2-bromoethoxy)-tert-butyldimethylsilane (534 μl, 3.32 mmol) was added to the mixture which was then stirred at room temperature for two hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product, tert-butyldimethyl-[2-(2-phenyl-[1,3]dioxan-5-yloxy)ethoxy]silane (343 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([OH:16])=[C:9]3[C:8]2=[O:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([O:16][C:15]1[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)[C:8](=[O:22])[C:9]=12)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (8.2 g, 24.6 mmol) in DMF (200 mL), cesium carbonate (10.4 g, 32.0 mmol) and benzyl bromide (3.2 mL, 27.1 mmol) were added. The reaction mixture was stirred at room temperature over night. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between ethyl acetate and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexanes and ethyl acetate gradient to give titled material.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1)#[N:24]
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound is prepared by hydrolysis of 9d using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1>CC(O)C.CS(C)=O>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:6][CH:5]=1)[CH2:3][N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1
Reactant: O=C(O)CC1CNCCO1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C(O)CC1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CCO1
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (25 mg, 0.063 mmol) in 2-propanol (2 mL) and DMSO (1 mL) was added 2-(morpholin-2-yl)acetic acid (18.18 mg, 0.125 mmol). The reaction mixture was hated at 80° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the desired product was 12.8 mg, and its purity was 99%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.28 Hz), 7.38-7.86 (7H, m), 5.03 (1H, ddd, J=9.03, 4.39, 4.14 Hz), 3.97-4.11 (1H, m), 3.90 (1H, t, J=9.66 Hz), 3.69-3.84 (1H, m), 2.97-3.21 (2H, m), 2.69-2.93 (2H, m), 2.18-2.63 (4H, m). MS (m+1)=545.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:13][C@:14]12[CH2:30][CH2:29][C@H:28]3[C@@H:19]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=43)[C@@H:18]1[CH2:17][CH2:16][C:15]2=O.C1COCC1>CO>[CH2:1]([NH:8][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:14]12[CH3:13])[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:21][CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1CCC2=O
Reactant: NCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1CC[C@@H]2NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzylamine (11.2 ml) in dry methanol (75 ml) was added sequentially acetic acid (6.16 ml), estra-1,3,5(10)-trien-17-one (5.21 g) sodium cyanoborohydride (1.35 g), and THF (60 ml) under a N2 atmosphere. The resulting mixture was stirred overnight at room temperature, concentrated in vacuo, diluted with water (200 ml), and made alkaline with aqueous sodium hydroxide (50 ml). The suspension was extracted with ethyl acetate (3×200 ml) and the combined extracts were dried over MgSO4, filtered and concentrated to an oil. This product was chromatographed (300 g silica gel 0.4-4-96 Et3N-acetone-hexane, 20 ml fractions) and gave impure product in fractions 53-79 and pure product in fractions 80-135. The latter were combined and after removal of the solvent gave the title compound as crystals, mp 71°-74° C. (PLA2, diabetes)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)=[CH:2]1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.C(Cl)Cl>CCOC(C)=O>[OH:18][C:12]1[CH:17]=[CH:16][C:15]([SH:1]2[CH:5]=[CH:4][C:3]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:2]2)=[CH:14][CH:13]=1
Reactant: C1=C(c2ccsc2)CCCC1
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc([SH]2C=CC(C3CCCCC3)=C2)cc1
Temperature: 70 °C

Procedure:
Thiophene-3-yl cyclohexene (72.3 mg, 0.44 mmol), and phenol (82.8 mg, 0.88 mmol) was mixed and gently heated until uniform and BF3*H3PO4 (4 uL, 0.044 mmol) was added. The mixture was heated at 70° C. overnight and the dark residue was diluted with EtOAc, washed with sat. NaHCO3, dried and concentrated. Column chromatography (silica, 0-20% EtOAc) gave a mixture of isomers and the desired product could be isolated by preparative TLC (DCM eluent). Yield: 3.7 mg, off-white/pale yellow solid. GC-MS: M+=258.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2COCC[Si](C)(C)C)=[C:7]([O:22][CH2:23][CH:24]2[CH2:28][O:27]C(C)(C)[O:25]2)[CH:6]=1.O.Cl>CO>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7]([O:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[CH:6]=1
Reactant: CC1(C)OCC(COc2cc(Oc3ccc(F)cc3F)cc3c2cnn3COCC[Si](C)(C)C)O1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCC(O)COc1cc(Oc2ccc(F)cc2F)cc2[nH]ncc12
Temperature: 90 °C
Yield: 86.7 %

Procedure:
6-(2,4-Difluoro-phenoxy)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.905 g, 1.79 mmol) was dissolved in 20 mL of MeOH. Water (12 mL) and concentrated HCl (12 mL) were added, and the reaction mixture was sealed and heated to 90° C. for 30 minutes. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was taken up in MeOH, made pH neutral by dropwise addition of aqueous NH4OH solution, and concentrated to dryness under reduced pressure. The residue was chromatographed through silica (0%-1 0% EtOAc in hexanes) to give 0.522 g of 3-[6-(2,4-difluoro-phenoxy)-1H-indazol-4-yloxy]-propane-1,2-diol, MS(M+H)=337.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=[CH:3]1.[CH:11]([N:14]=[C:15]=[S:16])([CH3:13])[CH3:12].Cl>C(#N)C.C(O)C>[ClH:1].[CH:11]([NH:14][C:15]([N:7]1[CH2:8][CH2:9][C:10]2[NH:2][CH:3]=[N:4][C:5]=2[CH2:6]1)=[S:16])([CH3:13])[CH3:12]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(C)N=C=S
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CC(C)NC(=S)N1CCc2[nH]cnc2C1
Yield: 76.5 %

Procedure:
A solution of 2 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride and 2.5 g of isopropyl isothiocyanate in 20 ml of acetonitrile and 5 ml of ethanol is refluxed 8 h. Evaporation of the solvent leaves a residue that is treated with one equivalent of ethanolic hydrogen chloride. Evaporation of the solvent leaves a residue which is crystallized from acetone to give 2.5 g of 5-(N-isopropyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 170°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)(C)(C)C>C(O)=O>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Oc3ccnc(C#N)n3)c2)cc1
Solvent: O=CO
Product: N#Cc1nccc(Oc2cccc(-c3ccc(CN)cc3)c2)n1

Procedure:
A solution of [3′-(2-cyano-pyrimidin-4-yloxy)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (10 mg) in formic acid (0.154 ml) is stirred at rt for 1 h. This solution is evaporated under reduced pressure. The remaining oil is treated with diethyl ether to obtain crystals of 4-(4′-aminomethyl-biphenyl-3-yloxy)-pyrimidine-2-carbonitrile as salt with formic acid.
Reaction SMILES: OO.[NH2:3][C:4]1[CH:11]=[C:10]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:25]4[NH:29][C:28]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:27]=5[N:26]=4)[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].CS(C)=[O:37].[OH-].[Na+]>C(O)C.O>[NH2:3][C:4]1[CH:11]=[C:10]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:25]4[NH:29][C:28]5[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:27]=5[N:26]=4)[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:5]=1[C:6]([NH2:7])=[O:37]
Reactant: N#Cc1ccc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)cc1N
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(-n2c3ccccc3c3c(-c4nc5ccc(F)cc5[nH]4)cccc32)cc1N

Procedure:
In a 50 ml round-bottomed flask, 0.2 ml of 30% aqueous hydrogen peroxide is added to a mixture of 40 mg of 2-amino-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]benzonitrile, obtained in the preceding stage, in 1.0 ml of ethanol and 0.4 ml of dimethyl sulphoxide and 0.2 ml of 1M sodium hydroxide, and the mixture is stirred for ¼ hour at ambient temperature. 20 ml of distilled water are added and the mixture is extracted with 3 times 30 ml of ethyl acetate. The combined organic phases are washed with 30 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (95/5 by volume). 24 mg of 2-amino-4-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]benzamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC4C=CC=CC=4)=[O:33])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1CC=CCC=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)OCc3ccccc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)O)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of benzyl 5-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)pentanoate (151 mg, 0.220 mmol) in ethanol (4.1 mL) was treated with 10% palladium on carbon (51 mg, 0.048 mmol) and 1,4-cyclohexadiene (0.23 mL, 2.4 mmol). The mixture was heated at 85° C. until the starting material was consumed as indicated by HPLC. After about 1 h, the starting material was consumed as indicated by HPLC and the reaction mixture was cooled to room temperature. The mixture was filtered through a pad of celite and the pad was washed with 40 mL EtOH. The solution was concentrated to yield the title compound (136 mg, 104%) as a nearly colorless glass, which was taken up in toluene, concentrated and placed under high vac. The material was determined to be of sufficient purity to be used in the next step without purification: MS (ESI+) for C31H43N5O7 m/z 598.7 (M+H)+; HPLC purity>95% (ret. time, 2.84 min).
Reaction SMILES: Cl.[CH2:2]([N:5]([CH:7]1[CH2:10][CH2:9][CH2:8]1)[NH2:6])[CH:3]=[CH2:4].[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O)=[O:15])[CH3:12].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[NH:6][N:5]([CH2:2][CH:3]=[CH2:4])[CH:7]1[CH2:10][CH2:9][CH2:8]1)=[O:15])[CH3:12]
Reactant: C=CCN(N)C1CCC1
Reactant: CCOC(=O)C1CCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: C=CCN(NC1CCCC1C(=O)OCC)C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
N′-Allyl-N′-cyclobutyl-hydrazine hydrogen chloride (288 mg, 1.77 mmol) was dissolved in methanol (20 mL). 2-Oxo-cyclopentanecarboxylic acid ethyl ester (0.26 mL, 1.77 mL), sodium acetate (290 mg, 3.54 mmol), sodium cyanoborohydride (222 mg, 3.54 mmol) and 4 Å molecular sieves (400 mg) were added sequentially. The reaction was stirred at 25° C. for 18 h before it was quenched via the addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes) afforded the desired product, 2-(N′-allyl-N′-cyclobutyl-hydrazino)-cyclopentanecarboxylic acid ethyl ester (333 mg, 1.25 mmol, 71%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.25-1.38 (2.2H, m), 1.60-1.68 (3.1H, m), 1.74-1.88 (5.2H, m), 1.94-2.06 (4.8H, m), 2.14-2.21 (3.6H, m), 3.42 (2.5H, d, J=6.8 Hz), 3.51-3.58 (1.3H, m), 3.64-3.69 (0.4H, m), 3.76-3.80 (0.5H, m), 4.10-4.20 (1.2H, m), 4.36-4.41 (0.3H, m), 5.36 (2.2H, bs), 5.45-5.51 (2.7H, m), 5.74-5.85 (1H, m). LC-MS (ESI) calcd for C15H26N2O2 266.38, found 267.2 [M+H+].