Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:32]1[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1>>[CH3:48][N:47]([CH3:49])[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([C:33]2[C:32]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:22]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)(=[O:23])=[O:24])[C:9]([C:11]5[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[CH:13][CH:12]=5)=[CH:10][C:3]=34)=[CH:36][N:35]([CH2:37][CH3:38])[N:34]=2)=[CH:40][CH:41]=1)=[O:50]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CS(=O)(=O)Nc1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(NS(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with N-{4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanesulfonamide. Using this product crude and following the procedure described in Intermediate 100 with N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 684.6
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2Br)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Solvent: CCN(CC)CC
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(N2CCOCC2)sc2c1CCCC2=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 58) (80 mg), triethylamine (29 mL) and morpholin (24 μL) were stirred at 60° C. for 3 hours. The residue resulting from the evaporation of the solvent at reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (82 mg) was obtained as a colorless candy-like substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.CS(O[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)(=O)=O>>[O:44]1[CH2:45][CH2:46][CH:41]([N:34]2[CH:35]=[C:31]([C:9]3[C:8]4[C:3]([O:2][CH:1]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[N:4][CH:5]=[CH:6][C:7]=4[NH:11][N:10]=3)[CH:32]=[N:33]2)[CH2:42][CH2:43]1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OC1CCOCC1
Product: c1cc2[nH]nc(-c3cnn(C4CCOCC4)c3)c2c(OC2CCOCC2)n1
Yield: 41 %

Procedure:
Prepared according to the general procedure described in example 92, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with tetrahydro-2H-pyran-4-yl methanesulfonate to give the title compound (26.5 mg, 41% over two steps). LC-MS (Method G): m/z=300.1 [M+H]+; 3.09 min. 1H-NMR (400 MHz, DMSO): δ 13.26 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.85 (d, J=5.3, 1H), 7.08 (d, J=5.6, 1H), 4.51 (s, 1H), 4.06 (s, 3H), 4.04-3.93 (m, 2H), 3.58-3.44 (m, 2H), 2.13-1.92 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC>>[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][O:22][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:23][CH:24]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCCO)cc1
Solvent: CCN(CC)CC
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenoxy]-ethanol (10) (200 mg, 0.62 mmol), methanesulfonyl chloride (0.05 ml, 0.62 mmol) and Et3N (0.09 ml, 0.62 mmol) was stirred at room temperature for 2 h. Then the reaction was quenched by addition of CH2Cl2 and water. The organic layer was then extracted with water and NaCl-solution, dried over Na2 SO4 and evaporated. The crude product was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]2=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred suspension of 4-methyl-3-nitro-2-pyridone (2.0 g, 13 mmol) in DMF (60 mL) was added NaH (60% suspension in oil, 0.52 g). After 1 hour, 4-methoxybenzyl chloride (1.8 mL) was added, and the mixture was stirred at rt overnight. Ethyl acetate was added, and the organic phase was washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (2.0 g, 7.3 mmol, 56%).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:15].[C:16]1([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH3:14][S:11]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:2]3[S:24][C:23](=[N:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:3]3([OH:15])[C:4]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc2c(c1)C(=O)C(Br)C2
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)C1(O)C(C2)SC(=Nc2ccccc2)N1c1ccccc1
Reaction time: 8 h

Procedure:
1.45 g of 2-bromo-6-methanesulfonylindan-1-one are dissolved in 15 ml of acetone and treated with stirring with 1.25 g of N,N'-diphenylthiourea in 25 ml of acetone. The hydrobromide of 5-methanesulfonyl-3-phenyl-2-phenylimino-2,3,8,8a-tetrahydro-indeno[1,2-d]thiazol-3a-ol crystallizes out of the clear solution after about 2 hours. After standing overnight, it is filtered off with suction and washed with a little acetone. 1.7 g of hydrobromide (m.p. 247° C.) are dissolved in 10 ml of methanol and treated with 0.8 ml of triethylamine. After 15 min, 150 ml of water are added and the mixture is stirred for 30 min with ice-cooling. The product formed is filtered off with suction and washed with a little cold water. 5-Methanesulfonyl-3-phenyl-2-phenylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol of melting point 172° C. is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([OH:24])[C@H:15]([NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21])[CH2:16][F:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:21][CH:20]([Cl:22])[C:19]([NH:18][C@H:15]([CH2:16][F:17])[C@H:14]([OH:24])[C:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:7][C:3]([CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][CH:5]=2)=[CH:13][CH:12]=1)=[O:23]
Reactant: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a suspension of N-((1R,2S)-1-(4-(5-(aminomethyl)thiophen-2-yl)phenyl)-3-fluoro-1-hydroxypropan-2-yl)-2,2-dichloroacetamide (150 mg, 0.383 mmol) in dichloromethane is added triethylamine (160 μL, 1.15 mmol) followed by methanesulfonyl chloride (30 μL, 0.383 mmol). Resulting yellow solution is stirred at room temperature for 30 minutes. The reaction is concentrated then purified using HPLC to give the title compound (99 mg): 1HNMR (400 MHz, DMSO-d6): δ 8.58 (d, 1H), 7.71 (t, 1H), 7.55 (d, 2H), 7.37 (d, 2H), 7.33 (d, 2H), 7.01 (d, 1H), 6.51 (s, 1H), 5.95 (br s, 1H), 4.85 (d, 1H), 4.71-4.52 (m, 1H), 4.44-4.13 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]5[C:41]=4[N:40]=[CH:39][CH:38]=[CH:37]5)(=[O:31])=[O:30])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:42].C(=O)([O-])[O-].[NH4+:47].[NH4+]>C(O)C>[ClH:42].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([S:29]([C:32]4[CH:33]=[CH:34][CH:35]=[C:36]5[C:41]=4[N:40]=[CH:39][CH:38]=[CH:37]5)(=[O:30])=[O:31])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)(=[NH:47])[NH2:2]
Reactant: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C#N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C(=N)N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino)-quinoline and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: [C-]#N
Reactant: Nc1nc(Cl)nc(N2CCc3ccccc32)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc(N)nc(N2CCc3ccccc32)n1
Reaction time: 2 h
Yield: 26.2 %

Procedure:
4-Chloro-6-(2,3-dihydro-indol-1-yl)-[1,3,5]triazin-2-ylamine (Intermediate 40, 680 mg, 2.48 mmol), potassium cyanide (323 mg, 4.96 mmol) and 18-crown-6 (328 mg, 1.24 mmol) were charged to a round-bottomed flask then taken up in DMF (12 mL). The resulting mixture was lowered into a heating block preheated to 110 C and stirred under nitrogen for 2 h and then at room temperature for 56 h. The reaction was then diluted with EtOAc (60 ml) and extracted with 5% aq. sodium carbonate solution (2×10 ml), brine (10 ml) and dried further over anhydrous magnesium sulfate. After evaporation of the solvent the crude residue was purified by FCC over silica gel eluting with heptane:EtOAc 1:0 to 8:2 to 1:1 to 0:1 and the column flushed with THF to give the title compound (155 mg, 26%). Method B HPLC-MS: MH+ requires m/z=239. Found: m/z=239, Rt=1.36 min (75%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[N:22]1(O)C2C=CC=CC=2N=[N:23]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:22]([C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[NH2:23]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.60 g), 1H-1,2,3-benzotriazol-1-ol (0.28 g) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.40 g) at room temperature. The mixture was stirred for 10 min and hydrazine monohydrate (0.28 mL) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.28 g, yield 44%) as colorless crystals. melting point>276° C. (decomposition).
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:34]([O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:33][C:17]=1[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:17]2[CH:33]=[C:34]([CH:35]=[CH:36][C:16]=2[Cl:15])[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:20]([CH3:32])=[C:21]3[CH3:31])=[O:29])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)Oc1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropoxyphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:17]=1)[C:5]2([CH3:25])[CH3:24].[C:26](Cl)(=[O:28])[CH3:27].O>C(Cl)Cl>[C:26]([N:21]1[CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([N:6]3[C:5]([CH3:25])([CH3:24])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[CH:13]=[N:14][CH:15]=2)[CH2:19][CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CCNCC2)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 5-chloro-3,3-dimethyl-2-(5-piperazin-1-yl-pyridin-3-yl)-2,3-dihydro-isoindol-1-one (52 mg, 0.146 mmol) and TEA (29.5 mg, 0.292 mmol) in DCM (5 mL) was added acetyl chloride (17.2 mg, 0.219 mmol) dropwise at 0° C. After stirring for 1 hour at room temperature, the mixture was treated with water and extracted with DCM. The organic layer was dried over anhy. Na2SO4. After removal of solvent, the residue was purified by preparative HPLC to afford the title compound as a white solid (23 mg, 40%). MS: 399.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]([F:25])([F:26])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:35]([CH3:34])(=[O:37])=[O:36])[C:21]([F:23])([F:22])[F:24])=[CH:11][CH:10]=1)([O:8][S:35]([CH3:34])(=[O:37])=[O:36])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(c1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
4.1 g (10 mmol) of 1,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 48 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). 3.2 g of 1,4-bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-benzene were obtained (colorless crystals, m.p.: 151° C. [from diisopropyl ether]).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1>C1COCC1>[CH3:23][O:22][C:18]1[N:17]=[C:16]([CH2:13][C:12]#[N:14])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(Br)n1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CC#N)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
1.6M n-Butyllithium/hexane solution (300 mL, 479.43 mmol) was added to a solution of acetonitrile (21.87 g, 532.70 mmol) in THF (630 mL) at −78° C. under argon atmosphere, and the mixture was stirred at −78° C. for 30 min. 2-Bromo-6-methoxypyridine (25.04 g, 133.18 mmol) was added dropwise thereto over 15 min at −78° C., and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (900 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→20% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)acetonitrile (11.37 g, 77 mmol, 58%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[N:11]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[N:11][N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CNc1ncc(Br)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nnc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 1.2 g, 5.94 mmol) in 2 M aqueous HCl (70 ml) cooled with an ice-bath was added a solution of sodium nitrite (Fluka, Buchs, Switzerland, 492 mg, 7.13 mmol) in water (10 ml). The reaction mixture was stirred at 0° C. for 1 h and at rt for 75 min then basified with 2 M aqueous NaOH (75 ml) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0%-30%) to give the title compound as a blue solid. (HPLC: tR 2.46 min (Method A); M+H=213, 215 MS-ES).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:24][C:25]3[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=3)=[N:3][CH:4]=[C:5]([CH:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH3:17])[CH:6]=2)[N:9]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoro-5-(1-morpholinoethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.314 mmol), N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (0.084 g, 0.377 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (0.254 mL, 1.256 mmol) was then added to the solution in one portion. The now brugundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stir for 1 h. The reaction mixture was extracted with EtOAc (2×10 mL), CHCl3 (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (100 mg). MS (ESI pos. ion) m/z: 520.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.58 Hz, 3H) 2.33 (br. s., 2H) 2.46 (s, 5H) 3.13 (s, 3H) 3.46 (d, J=4.82 Hz, 1H) 3.57 (br. s., 4H) 7.69-8.00 (m, 2H) 8.32 (s, 1H) 8.66 (d, J=2.48 Hz, 2H) 8.74 (s, 1H) 9.65 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH2:24](B(CC)CC)[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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](=[O:23])[C:5]1[C:10]([CH2:24][CH3:25])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Reactant: CCB(CC)CC
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(CC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 95 °C
Yield: 64.3 %

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (251 mg, 0.76 mmol), triethylborane (4.6 mL of 1 M solution in hexane, 4.6 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and Na2CO3 (1.27 g, 6 mL of 2M solution in H2O) in toluene (20 mL) is heated for 48 hours at 95° C. After cooling to room temperature the mixture is diluted with water (10 mL) and extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), concentrated, and purified by flash chromatography (elution with hexane/EtOAc 10:1) to yield 159 mg 6-(2,6-diethyl-phenyl)-4-ethyl-2-methyl-nicotinic acid ethyl ester as a colorless oil: 1H NMR (CDCl3) 7.29 (dd, 1H), 7.13 (d, 2H), 7.00 (s, 1H), 4.47 (q, 2H), 2.68 (q, 2H), 2.59 (s, 3H), 2.36-2.27 (m, 4H), 1.45 (t, 3H), 1.24 (t, 3H), 1.05 (t, 6H).
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7](Cl)[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([CH3:3])[CH3:2].[C:15]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)C1Cc2cccc(Cl)c2C1=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CC(C)C1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Temperature: 80 °C
Yield: 97.3 %

Procedure:
28.0 g of 2-isopropyl-7-chloro-1-indanone, 28.64 g of 4-tert-butylphenylboronic acid, 35.56 g of sodium carbonate, 302 ml of ethylene glycol and 21.6 ml of water are placed in a reaction vessel. The mixture is degassed a number of times by careful application of an oil pump vacuum and subsequent admission of argon, and thus saturated with argon. It is heated to 80° C. and a freshly prepared catalyst solution comprising 60.23 mg of palladium acetate and 1.79 ml of an aqueous TPPTS solution (0.6 molar) in 25 ml of water is then added while stirring vigorously and the reaction mixture is refluxed for 5 hours with further stirring until completely reacted. After cooling to room temperature, 300 ml of water are added. After renewed cooling to room temperature, the ethylene glycol phase is washed 6 times with a total of 900 ml of toluene. The combined toluene phases are washed twice with a total of 250 ml of sodium chloride solution and dried over 150 g of sodium sulfate. Removal of the solvent on a rotary evaporator, drying of the residue and subsequent distillation in an oil pump vacuum gives 40 g (97%) of 2-isopropyl-7-(4′-tert-butylphenyl)-1-indanone as an orange-brown, viscous oil.