Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:45]([NH:48][CH2:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:47])[CH3:46]>ClCCl>[C:45]([NH:48][CH2:49][CH2:50][CH2:51][C:52]([O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])=[O:53])(=[O:47])[CH3:46]
Reactant: CC(=O)NCCCC(=O)O
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Reaction time: 0.42 h

Procedure:
To a suspension of hemiaminal A1 (2.6 g, 5.5 mmol) in dichloromethane (30 mL) was added triethylamine (2.3 mL, 16.4 mmol), followed by addition of methanesulfonyl chloride (0.47 g, 6.0 mmol) over 3 min. The reaction mixture was stirred for 25 min and then N-acetyl-4-aminobutyric acid (1.6 g, 10.1 mmol) added. The reaction mixture was then heated at reflux for 18 h, cooled and washed with sat. NaHCO3 (aq). The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with 1:1:0.1 to 1:1:0.2 dichloromethane/ethyl acetate/methanol to give the title compound as an off white solid (1.1 g, 34%).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([O-:11])([O-])=[O:9].[K+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[CH:23][C:22]=1[F:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][C:21]1[C:22]([F:36])=[CH:23][C:24]([NH:27][C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[C:25]([N+:8]([O-:11])=[O:9])[CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)c1cnccn1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 ml of trifluoroacetic acid and 1.99 g of potassium nitrate were added to a chloroform (40 ml) suspension of 5.80 g of N-(4-benzyloxy-3-fluorophenyl)pyrazinecarboxamide, with cooling with ice, and the reaction liquid was stirred overnight at room temperature. The solvent was evaporated away under reduced pressure, and aqueous saturated sodium bicarbonate was added to it. The resulting solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)\[C:5]#[N:6].C(O)(=[O:15])C.OO>O>[CH3:1][O:2]/[N:3]=[C:4](/[C:7]1[CH:12]=[N+:11]([O-:15])[CH:10]=[CH:9][N:8]=1)\[C:5]#[N:6]
Reactant: CO/N=C(\C#N)c1cnccn1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: CO/N=C(\C#N)c1c[n+]([O-])ccn1
Temperature: 70 °C

Procedure:
A mixture of Z-α-methoxyiminopyrazineacetonitrile (4 g), acetic acid (15 ml) and 30% hydrogen peroxide in water (15 ml) was heated at a temperature of 70° C. over one night. The reaction mixture was concentrated and treated with water and chloroform. The chloroform layer was separated and dried over magnesium sulphate. Evaporation of the solvent and successive crystallization of the residue from alcohol afforded Z-α-methoxyimino-2-pyrazineacetonitrile-4-oxide, m.p. 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11].ClC1C(C)=C(N=[C:23]=[O:24])C=CC=1C#N>>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11])=[C:23]=[O:24]
Reactant: N#Cc1ccc(N)c(F)c1Cl
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Product: N#Cc1ccc(N=C=O)c(F)c1Cl

Procedure:
4-Isocyanato-3-fluoro-2-chlorobenzonitrile was prepared from 4-amino-3-fluoro-2-chlrorbenzonitrile (9B) in a manner similar to that described in Example 1 for the preparation of 1G.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:16][C:15]=2[F:33])=[O:12])[N:7]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][N:39](C(OCC2C=CC=CC=2)=O)[CH2:38][CH2:37]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH:22]=3)=[CH:16][C:15]=2[F:33])=[O:12])[N:7]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH2:40][NH:39][CH2:38][CH2:37]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc5c(c4)CCN(C(=O)OCc4ccccc4)C5)c(F)c3)ccn2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc5c(c4)CCNC5)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of benzyl 6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.14 mmol) in methanol/EtOAc (1:1, 10 mL) was added 10% Pd/C. The solution was stirred overnight under H2 (1 atm) at RT. The solution was filtered and concentrated in vacuo to obtain 1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (73 mg, 90% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.00 (brs, 1H), 8.02 (m, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.15 (dt, J=2.4, and 8.8, 1H), 7.95 (s, 1H), 7.1-7.3 (m, 3H), 7.99 (m, 1H), 6.65 (m, 1H), 6.36 (d, J=2.8 Hz, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.53 (m, 1H), 3.01 (m, 1H), 2.88 (m, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 1.25 (s, 9H); MS (ESI) m/z: 581.3 (M+H+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15](=[O:38])[O:16][C:17]1[CH:18]([CH2:31][CH:32]2[CH2:37][CH2:36][S:35][CH2:34][CH2:33]2)[NH:19][C:20](=[O:30])[C:21]=1[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:38])[O:16][C:17]1[CH:18]([CH2:31][CH:32]2[CH2:37][CH2:36][S:35](=[O:9])[CH2:34][CH2:33]2)[NH:19][C:20](=[O:30])[C:21]=1[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCSCC1
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of m-CPBA (189 mg, 1.1 mmol) in 5 ml of CH2Cl2 was added slowly to a stirred solution of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(tetrahydro-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (compound P1.2) (390 mg, 1.0 mmol) in 10 ml CH2Cl2 and the reaction mixture was stirred at room temperature for 1 h. Then, the resulting mixture was washed with saturated NaHCO3 (aq) and aqueous Na2S2O3, respectively. The organic layer was dried over sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by chromatography on silica gel. Yield: 100 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-5-oxo-2-(1-oxo-hexahydro-1λ4-thiopyran-4-ylmethyl)-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (compound P1.4) as a solid, mp 103-106° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>ClCCl>[C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20])[CH2:4]1)#[CH:2]
Reactant: C#CC1CCCNC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC1CCCN(S(=O)(=O)C(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of Example 10A (500 mg, 4.58 mmol) in dichloromethane (10 mL) was added triethylamine (2.55 mL, 18.32 mmol) followed by propane-2-sulfonyl chloride (1.306 g, 9.16 mmol) and the mixture was stirred for 3 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound. LCMS: 216.2 (M+H-Boc)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:14]OC(C)(C)C.CCCCCC>C(OCC)(=O)C>[Cl:14][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]([OH:12])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C)c1O
Reactant: CC(C)(C)OCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(O)c(Cl)cc(C(=O)O)c1O
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of 2,4-dihydroxy-3-methylbenzoic acid methyl ester (9.9 g) in ethyl acetate (100 ml) was added tert-butyl hypochlorite (12.3 ml) under ice-cooling. After stirring for 2 hours, hexane (200 ml) was added, and the mixture was cooled with ice to allow precipitation of crystals. The crystals were collected by filtration, and dissolved in a mixed solvent of methanol (20 ml) and tetrahydrofuran (THF, 20 ml). A 1 M lithium hydroxide solution (40 ml) was added to the solution, and the mixture was refluxed under heating for 18 hours. The reaction mixture was concentrated, and a 10% aqueous citric acid solution was added to the residue, which was followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (4.14 g, yield 37%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCNCC2)C3)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCN(c4ncc(C(F)(F)F)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 37, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyrimidine in dimethylsulfoxide at 110° C. in the presence of potassium carbonate. LC (method 5): tR=1.28 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: B.CSC.[CH:5]1([CH2:15][C:16](O)=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1>C1COCC1>[CH:5]1([CH2:15][CH2:16][OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: O=C(O)CC1OCCc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Borane-methyl sulfide (10.5 ml) in THF is added to an ice-cooled solution of (-)-(isochroman-1-yl)acetic acid (LXI, EXAMPLE 45--Step 3, 7.08 g, 36.8 mmol). After stirring for 20 min at 0°, the ice bath is removed and the solution is stirred at 20-25° for another 1.7 hr. The reaction flask is then placed in an ice-water bath and methanol is added slowly until no further gas evolution occurs. The solvents are then removed under reduced pressure and methanol is again added and removed a second and third time. The residue is partitioned between dichloromethane, aqueous sodium bicarbonate and saline. The organic phase is separated, dried over sodium sulfate and concentrated to give (-)-2-(isochroman-1-yl)ethanol (LXXIX). This material is added to dimethylaminopyridine (0.22 g, 1.8 mmol), diisopropylethylamine (16.0 ml, 92 mmol) and THF (60 ml). The mixture is cooled in an ice-water bath and methanesulfonyl chloride (3.4 ml, 44.2 mmol) is added dropwise over several minutes. After stirring for 55 min at 0°, 4-(piperazin-1-yl)benzamide (IV, EXAMPLE 47 Step 1, 9.06 g, 44.2 mmol) and ethylene glycol (60 ml) are added. The mixture is heated at 80° overnight and then water is added and the resulting solid is collected and washed with water and toluene. After drying, the solid is passed through silica gel using methanol/dichloromethane (4/96) to give (-)-4-[4-[2-(isochroman-1-yl)ethyl]piperazin-1-yl]benzamide, MS (m/z) 365; IR (mineral oil) 1610, 1239, 1643, 1112, 1622 cm-1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:25])[CH2:4][CH2:3]1.[O:26]=[C:27]1[CH2:32][O:31][C:30]2[CH:33]=[CH:34][C:35]([CH:37]=O)=[N:36][C:29]=2[NH:28]1.C([BH3-])#N.[Na+]>>[O:25]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:37][C:35]3[CH:34]=[CH:33][C:30]4[O:31][CH2:32][C:27](=[O:26])[NH:28][C:29]=4[N:36]=3)[CH2:7][CH2:6]2)[C:15]2[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(OC(F)(F)F)cc54)CC3)nc2N1
Yield: 15.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(trifluoromethoxy)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 61) (0.55 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (120 mg, 0.66 mmol) and sodium cyanoborohydride (69 mg, 1.1 mmol) were reacted as described under Example 21 to give 44 mg (15%) product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[N:28]1([C@H:32]2[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]2[F:38])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C@H:32]2[CH2:37][CH2:36][N:35]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:34][C@H:33]2[F:38])[CH2:29][CH2:30][CH2:31]1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: F[C@@H]1CNCC[C@@H]1N1CCC1
Product: F[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC[C@@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (cis)-4-azetidin-1-yl-3-fluoro-piperidine in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a tan solid (284 mg, 57%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]([O:15]CC)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2cccnc12
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NC[C@@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a stirred mixture of ethyl 2-(quinolin-8-yloxy)acetate (250 mg, 1.08 mmol) in EtOH (2 mL) was added (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (222 mg, 1.08 mmol). The mixture was stirred at 120° C. for 0.5 hour under microwave heating. After evaporation of the solvent, the residue was purified first by prep-TLC and then by prep-SFC to afford (160 mg Yield 40%). 1H NMR (400 MHz, MeOD) δ=8.791 (d, J=4.3 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 7.51-7.46 (m, 3H), 7.17 (d, J=7.3 Hz, 1H), 6.94-6.85 (m, 4H), 4.65 (s, 2H), 4.00-3.99 (m, 1H), 3.59 (s, 2H), 3.44-3.32 (m, 2H), 2.77-2.71 (m, 4H), 2.53-2.51 (m, 2H). LCMS (m/z): 392.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10](Cl)[C:11]([C:25]#[N:26])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1B(O)O.O1CCOCC1>C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10]([C:34]3[CH:33]=[C:32]([F:35])[CH:31]=[CH:30][C:29]=3[Cl:28])[C:11]([C:25]#[N:26])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2nc(Cl)c(C#N)c3c2c1NC(=O)N3c1ccncc1
Reactant: OB(O)c1cc(F)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2nc(-c3cc(F)ccc3Cl)c(C#N)c3c2c1NC(=O)N3c1ccncc1

Procedure:
7-chloro-6-cyano-4-oxo-5-pyridin-4-yl-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 3a (537 mg, 1.35 mmol), prepared using the procedure of Example 1, was combined with 2-chloro-5-fluorophenyl-boronic acid (468 mg, 2.69 mmol), Pd(Ph3P)4 (156 mg, 0.135 mmol), sat'd NaHCO3 (15 mL) and 1,4-dioxane (40 mL). The reaction mixture was refluxed for 2 hrs then diluted with sat'd NaHCO3 and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated. The solid was recrystallized from EtOAc to give 7-(2-chloro-5-fluoro-phenyl)-6-cyano-4-oxo-5-pyridin-4-yl-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 15 (440 mg) as a pale yellow solid. LC/MS 494, 496 (MH+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]5[OH:65])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCC[C@@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and cis-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.93 (m, 18H) 3.31 (s, 3H) 3.73-3.91 (m, 2H) 3.95 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.47 (m, 1H) 4.70 (br. s., 1H) 7.47 (d, J=8.0 Hz, 1H) 7.53 (s, 1H) 7.79 (d, J=7.83 Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H). [M+H] calculated for C28H36F2N6O4, 559. found 559.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[CH2:11]([O:18][C:19]1[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:46]=[C:45]([O:47][CH2:9][CH2:8][Br:7])[CH:44]=[CH:43][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OCCBr)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
Potassium carbonate (1.6 g) and 1,2-dibromoethane (2.6 mL) were added to a N,N-dimethylformamide (5.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamido)-4-phenylbenzoate (0.29 g), followed by stirring at 120° C. for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-91% hexane/ethyl acetate] to obtain 0.19 g of tert-butyl 2-(2-(benzyloxy)-4-(2-bromoethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:12][C@@H](C)CSC)[O:5][C:6]2=[O:11].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CC1C=CC([NH2:28])=C(C)C=1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH2:28])(=[O:11])[C:7]1[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=1)[C:4]([NH2:12])=[O:5]
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Reactant: CSC[C@H](C)N=C1OC(=O)c2cccc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
4-Chloro-3-[(S)-1-methyl-2-methylthioethylimino]-3-H-isobenzofuran-1-one (0.2 g) and 4-(3,5-bis-trifluoromethyl-benzyl)-2-methylaniline (0.22 g) were dissolved in acetonitrile (10 ml), to which p-toluenesulfonic acid hydrate (0.01 g) was added, and then stirred at room temperature for three hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bis-trifluoromethyl-benzyl)-2-methylphenyl]-3-chloro-N2-(S)-1-methyl-2-methylthioethyl)phthalamide (0.10 g).
Reaction SMILES: B.CSC.[C:5]([C-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(=[O:7])[CH3:6].[C-:13]1([C:18](=[O:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:21]>O1CCCC1>[OH:7][C@@H:5]([C-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[CH3:6].[C-:13]1([C@H:18]([OH:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:21]
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](O)[c-]1cccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
11.5 ml (115 mmol) of borane-dimethyl sulphide adduct were added dropwise at 20° C. to a solution of 30.0 g (111 mmol) of 1,1'-diacetylferrocene and 13.5 ml (13.5 mmol, 0.12 eq) of catalyst (S)-III (R6 =CH3) in 200 ml of tetrahydrofuran over a period of 45 minutes. After 1 hour at 20°-25° C., the reaction mixture was poured while stirring vigorously onto about 600 ml of ice/water and stirred for 0.5 hour. The aqueous phase was subsequently extracted three times with 200 ml each time of tert-butyl methyl ether, the combined organic phases were dried over magnesium sulphate and evaporated in a high vacuum. This gave 32.7 g (107%) of the crude title compound. This crude product can be used without further purification for the further reactions. Recrystallization from hexane gave (R,R)-1,1'-bis(1-hydroxyethyl)ferrocene as a yellow crystalline solid.