Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=O.[C:14](#[N:17])[CH:15]=C.C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>C1(=O)CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH:4]=[CH:15][C:14]#[N:17]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Reactant: C=CC#N
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Solvent: O=C1CCCC1
Product: Cc1ccc([N+](=O)[O-])cc1C=CC#N
Yield: 22.3 %

Procedure:
0.2877 g (0.5 millimol) of bis-(dibenzylideneacetone)-palladium(O), 9.98 g (50 millimols) of 2-methyl-5-nitrobenzoyl chloride, 3.31 g (62.5 millimols) of acrylonitrile and 17.68 g (50 millimols) of tris-(2-ethylhexyl)-amine, in 100 ml of cyclopentanone, are stirred for 1.5 hours at 100° C. The crude product is chromatographed on silica gel, in methylene chloride, and is then recrystallised from cyclohexane/carbon tetrachloride. 2.1 g (24% of theory) of 2-methyl-5-nitrocinnamonitrile are obtained in the form of white crystals; melting point 113.2° C.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:19])[O:17][CH3:18]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:18][O:17][C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)=[O:19]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
From 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and methyl chlorocarbonate in a mixture of dioxane and toluene, 4,9-dihydro-4-methoxycarbonyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained;
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O.[CH3:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH3:22][N:23]([CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (Step 1)(0.6 g, 2.1 mmol), was added dimethylamine (Aldrich) (1.6 mL of a 2.0 M soln in THF, 3.2 mmol) in ClCH2CH2Cl (15 mL) and NaBH(OAc)3 (Aldrich) (0.66 g, 3.2 mmol). The reaction was stirred at RT for 2 h. The mixture was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[(dimethylamino)methyl]phenyl}piperazinecarboxylate (0.68 g) as a yellow oil. MS m/z: 320 (M+H). Calc'd for C18H29N3O2: 319.44.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:17])[CH3:2].Br[CH2:27][C:28]1[C:32]2[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[S:30][N:29]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:27][C:28]2[C:32]3[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=3[S:30][N:29]=2)[C:7]1=[O:17])[CH3:2]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 66.9 %

Procedure:
To a solution of (S)-(4-Chloro-phenyl)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid ethyl ester (50 mg, 0.14 mmol) (prepared according to example 1, steps 1-3) in DMF (10 mL) are added 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (54 mg, 0.21 mmol) (prepares according to example 5, steps 1-6) and K2CO3 (58 mg, 0.42 mmol) at room temperature under nitrogen atmosphere. The solution is heated to 100° C. for 2 hours. The solution is cooled down and water is added. The solution is extracted with EtOAc and the combined organic layer is dried with MgSO4. The solution is filtered and the filtrate is concentrated. The residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford (S)-(4-Chloro-phenyl)-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid ethyl ester (50 mg, 67%) as a colorless foam.
Reaction SMILES: [OH-].[K+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>O>[CH3:13][CH:14]1[CH2:18][CH2:17][C:16](=[CH:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[C:15]1=[O:19]
Reactant: COc1ccc(C=O)cc1
Reactant: CC1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C=C2CCC(C)C2=O)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 2.8 g of 85% strength potassium hydroxide and 250 ml of water was charged to a stirred 3-necked flask apparatus with reflux condenser, 68 g of p-anisaldehyde and 49 g of 2-methylcyclopentanone were added, and the mixture was boiled under reflux for 3 hours. It was subsequently cooled to room temperature and the yellow solid which had crystallized out was filtered off with suction, washed to neutrality with water and dried in a vacuum oven at 60° C. In this way 98.3 g of 2-methyl-5-(4-methoxybenzylidene)-cyclopentanone (93.2% pure) were obtained. This corresponds to a yield of 85% of theory.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]2[O:13][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)=[CH:2]1.[OH-:19].[Na+]>CO>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:19])=[O:14])=[O:13])=[CH:2]1
Reactant: [OH-]
Reactant: O=c1oc(C=Cc2ccsc2)nc2ccccc12
Agent: [Na+]
Solvent: CO
Product: O=C(C=Cc1ccsc1)Nc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 96 %

Procedure:
To 2-[2-(3-thienyl)vinyl]-4H-3,1-benzoxazine-4-one (800 mg, 3.13 mmol) was added 1N-NaOH (21.9 ml) and the mixture was heated to 70° C. After adding methanol (30 ml), and the mixture was reacted for 1 hour. The methanol was removed from the reaction mixture under reduced pressure, and the residue was acidified with 10% HCl under cooling (pH about 4) to give a white solid, which was collected on a filter, washed with water, and dried to give the title compound (826 mg, yield, 96%). m.p., 218°-219° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[CH:24]=2)[C:8](=[O:22])[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]=1)(=[O:3])[CH3:2].[Cl:32]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClCCl.C(OCC)C>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:31])=[O:30])[CH:24]=2)[C:8](=[O:22])[C:9]([Cl:32])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(C(N)=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cccc(C(N)=O)c1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
{1-[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo-1,6-dihydropyridin-2-yl}methyl acetate (from step 2) (1.02 g, 2.39 mmol) was suspended in dichloromethane (15 mL) and N-chlorosuccinimide (0.37 g, 2.75 mmol) was added. Dichloroacetic acid (0.10 ml, 1.22 mmol) was added and the reaction mixture was stirred at 40° C. for 1.5 hours. The reaction was cooled to room temperature and a precipitate formed. The reaction mixture was diluted with diethyl ether and the precipitate was collected by filtration and washed with diethyl ether (3×15 mL) to afford a tan solid (0.940 g, 85%). 1H NMR (400 MHz, DMF-d6) δ 8.21 (br s, 1H), 8.11 (app dt, J=1.48, 7.52 Hz, 1H), 7.95 (app t, J=1.61 Hz, 1H), 7.80 (app dt, J=6.72, 8.59 Hz, 1H), 7.69-7.60 (m, 2H), 7.48 (br s, 1H), 7.35 (ddd, J=2.55, 9.53, 10.61 Hz, 1H), 7.24-7.19 (m, 1H), 6.97 (s, 1H), 5.49 (s, 2H), 4.71 (AB q, JAB=15.04 Hz, 2H), 1.98 (s, 3H). ES-HRMS m/z 463.0883 (M+H calcd for C22H17ClF2N2O5 requires 463.0867).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:6].ClC1C=C(Cl)C=C(Cl)C=1[O:24][C:25](=O)[CH:26]([CH3:39])[C:27](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:28]>BrC1C=CC=CC=1>[CH:8]1([N:7]2[C:25](=[O:24])[C:26]([CH3:39])=[C:27]([OH:28])[C:4]([C:3]([O:2][CH3:1])=[O:14])=[C:5]2[CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)C=C(C)NC1CCCCC1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Brc1ccccc1
Product: COC(=O)c1c(O)c(C)c(=O)n(C2CCCCC2)c1C
Temperature: 170 °C
Yield: 21.3 %

Procedure:
To a solution of 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) was added 2-methylmalonic acid bis-(2,4,6-trichloro-phenyl)ester (2.71 g, 5.72 mmol) and the reaction mixture was heated at 170° C. for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 94:6 methylene chloride/MeOH) and recrystallization from hot MeOH provided methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate as pale yellow crystals (0.34 g, 21%): 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 4.00-3.90 (m, 1H), 3.76 (s, 3H), 2.75-2.60 (m, 2H), 2.31 (s, 3H), 1.81 (s, 3H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 3H), 1.40-1.20 (m, 2H), 1.15-1.05 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]2)=[O:5])[CH3:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]2[N:23]([CH3:24])[CH:11]([CH2:12][C:13]=1[C:14]1[O:18][N:17]=[C:16]([CH2:19][CH2:20][CH2:21][O:22][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42])[CH:15]=1)[CH2:10][N:9]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2cc(CCCO)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2cc(CCCO[Si](C)(C)C(C)(C)C)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of compound B3 (3.56 g, 8.17 mmol), imidazole (1.39 g, 20.4 mmol), and TBDMS-Cl (1.85 g, 12.2 mmol) in DMF (70 mL) was stirred at 0° C. for 30 min, then at rt for 1 h. The mixture was diluted with EtOAc and washed with aq. 10% Na2CO3 (2×), and brine (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:6→1:3→1:1) yielded the title compound (2.47 g, 55%). LC-MS: tR=0.94 min; ES+: 550.40.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([C:4]4[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: COc1cccnc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 8 h
Yield: 32 %

Procedure:
3-(Methyloxy)-2-pyridinecarboxylic acid (available from Milestone Pharm Tech, 123 mg, 0.81 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (306 mg, 0.81 mmol) and DIPEA (0.422 ml) were stirred in DMF (2 ml) for 30 mins under nitrogen. Then 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.40 mmol) was added and the reaction was stirred overnight. The reaction was loaded onto an aminopropyl column and left for 3 h, before eluting with 10% MeOH in DCM. Appropriate fractions were combined and evaporated under vacuum. The residue was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (49 mg).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=1)=[O:16].[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](=[O:24])[NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:39])=[CH:20][CH:21]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Under an argon atmosphere 21.0 g (129 mmol) carbonyldiimidazol was added to a solution of 24.1 g (129 mmol) thiophene-2,5-dicarboxylic acid monomethyl ester in 600 ml THF. After 2 h at rt 26.9 g (129 mmol) (2-amino-phenyl)-carbamic acid tert-butyl ester were added and the reaction mixture was stirred for further 4 h at rt. The solvent was evaporated and the residue dissolved in 500 ml ethyl acetate. The organic phase was washed three times with 100 ml saturated aqueous NaHCO3 solution, twice with 80 ml water and was dried over sodium sulfate. The solvent was removed down to 80 ml when crystallization started. After 12 h the crystalls were filtered off and washed with little ice-cold t-butyl methyl ether and cold heptane. Drying under high vacuum yielded 38.9 g (103.4 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carbox-ylic acid methyl ester, 1H-NMR (D6-DMSO) δ=1.45 (s, 9H), 3.87 (s, 3H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m,1H), 7.59 (m, 1H), 7.89 (m, 1H), 7.96 (m, 1H), 8.73 (br, 1H), 10.02 (s, 1H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:13]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1cccc2ccccc12
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOc1cccc2ccccc12
Temperature: 25 °C
Yield: 98.4 %

Procedure:
1-naphthol (5 g, 34.7 mmol), iodohexane (8.82 g, 41.6 mmol) and K2CO3 (7.2 g, 50 mmol) in acetonitrile (150 ml) were refluxed overnight under N2. After being cooled to room temperature, water (10 ml) was added and acetonitrile was evaporated. Water (150 ml) and Et2O (150 ml) were added. The ethereal layer was extracted and washed with water (2×100 ml), brine (100 ml), dried over MgSO4, filtered and evaporated to dryness to afford 7.8 g (98%) of compound 2 as an orange oil after during at 80° C. under vacuum.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)[CH2:9]1)C1C=CC=CC=1.CCN(CC)CC.C(Cl)(=O)OC(Cl)C>C(Cl)Cl>[CH3:20][O:19][C:16]1[CH:17]=[N:18][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:14][CH:15]=1
Reactant: COc1cnc(C2CCN(Cc3ccccc3)C2)nc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cnc(C2CCNC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.8 %

Procedure:
To a solution of 2-(1-benzyl-pyrrolidin-3-yl)-5-methoxy-pyrimidine (100 mg, 0.37 mmol) and Et3N (37.6 mg, 0.37 mmol) in CH2Cl2 (2 mL) was added 1-chloroethyl carbonochloridate (63.8 mg, 0.45 mmol) dropwise at 0° C. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated to afford crude 5-methoxy-2-(pyrrolidin-3-yl)pyrimidine (100 mg), which was used for next step without purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:14])=[N:11][CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([C:7]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)[CH2:34][CH2:33]1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Reactant: CC1CCNCC1
Product: CC1CCN(c2ccc(C(=O)O)nc2)CC1

Procedure:
Benzhydryl 5-trifluoromethanesulfonyloxypyridine-2-carboxylate (3.0 g) was heated with 4-methylpiperidine (1.4 g) at 80° C. for one hour. The reaction mixture was immediately purified by preparative HPLC and then hydrogenated in analogy to method. This resulted in the product with the molecular weight of 220.27 (C12H16N2O2); MS (ESI): 221 (M+H+).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OC(=O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
The ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate (1.2 g, 2.9 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and then concentrated. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 0.63 g of ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate. Mass calculated for C18H19NO4=313.35. found: [M+H]+=314.1.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)(Cl)Cl>[N:1]1([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
A mixture of 3-pyrroline (9.1 g), N,N-diisopropylethylamine (28 mL), and chloroform (46 mL) was ice-cooled, benzyl chloroformate (26 g) was added dropwise, and then the mixture was stirred at room temperature for 15 h. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, and then dried with anhydrous sodium sulfate. The desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain benzyl 2,5-dihydropyrrole-1-carboxylate (26 g).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[C:19]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][C@@H:24]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.C(N(CC)CC)C.C1(N(C2C=CC=CC=2)C([NH:52][S:53](Cl)(=[O:55])=[O:54])=O)C=CC=CC=1.Cl>C1COCC1>[S:53](=[O:55])(=[O:54])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[C:20]([F:21])=[C:19]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][C@@H:24]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[OH:8])[NH2:52]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)c1F
Reactant: O=C(NS(=O)(=O)Cl)N(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)c1F
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)-oxy]cyclopentyl}methanol (190 mg, 0.36 mmol) in THF (5.40 mL) was added triethylamine (0.08 mL, 0.54 mmol) and [(diphenylamino)carbonyl]sulfamoyl chloride (186 mg, 0.54 mmol) at 0° C. under an atmosphere of Argon, and the mixture was stirred for 30 min. The reaction mixture was added 1.00 M Hydrochloric acid in (5.40 mL) at 23° C., and the resulting mixture was stirred for 16 h. The reaction mixture was quenched by addition of saturated NaHCO3 solution (80.0 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 0 to 10% methanol in DCM to afford the title compound (91.0 mg, 51%). 1H-NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.25-7.13 (m, 4H), 5.72 (d, 1H, 1=6.5 Hz), 5.65-5.58 (m, 1H), 4.43-4.38 (m, 1H), 4.33 (dd, 1H, J=9.7, 7.6 Hz), 4.22 (dt, 1H, J=5.0, 2.4 Hz), 4.16 (dd, 1H, J=9.7, 7.3 Hz), 3.35 (s, 3H), 3.14 (dd, 1H, J=16.6, 2.4 Hz), 3.02 (dd, 1H, J=16.6, 5.0 Hz), 2.60-2.49 (m, 1H), 2.31 (ddd, 1H, d=14.8, 6.8, 2.3 Hz), 2.12 (ddd, 1H, J=14.8, 5.0, 4.7), 2.08-1.95 (m, 2H). LC/MS: Rt=6.76, ES+ 469.3 (FA long).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[O:10][CH2:17][CH2:16][NH:12][CH2:13][CH2:14][O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCNCCO
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Fc1ccc(B2OCCNCCO2)cc1Cl
Yield: 87 %

Procedure:
The title compound (87%, oil) was prepared from 3-chloro-4-fluorophenylboronic acid and diethanolamin.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=1)[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O1CCCC1>[C:3]12([CH2:2][NH:1][C:15]3[C:14]([Cl:13])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(NCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 65 °C
Yield: 8.3 %

Procedure:
A stirred mixture of 1-(aminomethyl)adamantane (0.31 g, 1.85 mmol), 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (0.5 g, 1.85 mmol) and potassium carbonate (0.64 g, 4.63 mmol) in N,N-dimethylformamide (18 mL) and tetrahydrofuran (10 mL) was heated at 65° C. for 48 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with saturated aqueous ammonium chloride (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0 to 10% gradient of methanol in dichloromethane to afford the title compound as a pale yellow solid (0.064 g, 8%): 1H NMR (300 MHz, CDCl3) δ 8.55-8.08 (m, 2H), 7.51-7.40 (m, 1H), 6.58-6.43 (m, 1H), 3.44 (s, 3H), 2.84-2.75 (m, 2H), 2.02 (br s, 3H), 1.81-1.46 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 166.5, 162.5 (d, 1JC-F=255.0 Hz), 153.1 (d, JC-F=11.8 Hz), 130.9 (d, JC-F=3.2 Hz), 106.8, 106.2 (d, JC-F=19.5 Hz), 99.6 (d, 2JC-F=25.3 Hz), 55.7, 42.1, 40.6, 36.9, 33.8, 28.2; MS (ES+) m/z 414.8, 416.8 (M+1).