Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[O:12][CH2:13][CH3:14])[NH2:8])(=[O:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([NH:8][C:30](=[O:31])[O:32][CH:33]([CH3:35])[CH3:34])[CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[O:12][CH2:13][CH3:14])(=[O:3])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1cc(N)cc(OC(C)=O)c1OCC
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(NC(=O)OC(C)C)cc(OC(C)=O)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
3-Acetyloxy-4,5-diethoxyaniline (1.0 g) and N,N-diethylaniline (0.70 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.70 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-acetyloxy-4,5-diethoxyphenyl)carbamate (Compound No. 4) (1.21 g) in a yield of 88.9%. M.P., 108°-109° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.[OH:12][C:13]1[CH:22]=[C:21]([CH3:23])[C:16]2[NH:17][C:18](=[O:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=[C:2]([O:12][C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(C2CC2)n1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)nc(C3CC3)n2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.53 mmol) 4,6-dichloro-2-cyclopropylpyrimidine were added to 95 mg (0.55 mmol) 6-hydroxy-4-methylbenzo[d]oxazol-2(3H)-one and 0.21 g (0.63 mmol) caesium carbonate in 1.5 mL DMF after 15 min and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[S:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>CCOCC.C(Cl)Cl>[ClH:1].[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:10][NH:11][CH:19]([CH3:21])[CH3:20])[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[S:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:5][CH:4]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
HCl (4N in dioxane) was added to a solution of tert-butyl 2-(4-fluorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (50 mg, 0.092 mmol) in Et2O (4 mL) and DCM (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was taken up into DCM (1 mL), and precipitated with Et2O (15 mL), and the solids were filtered under nitrogen to give 2-(4-fluorophenyl)-3-(isopropylamino)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (30 mg, 63% yield) as a mixture of 2 diastereomers. LCMS (APCI+) [M+H]+ 444.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1nc2ccccc2o1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2nc3ccccc3o2)c(=O)[nH]c1=O
Yield: 59.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (241 mg, yield: 59.7%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (30.0 mg, 0.128 mmol) prepared in Process 3 of Example 12 in dichloromethane (3 mL) was added sequentially with 4-chlorophenyl isocyanate (19.7 mg, 0.128 mmol), triethylamine (19.4 mg, 0.192 mmol), DMAP (catalyst amount) at room temperature, and the resultant was stirred at the same temperature for 1.5 hours. The reaction solution was filtered using celite, concentrated in vacuo, and the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (49.7 mg, 100%) was obtained as a white crystalline powder.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:35]([OH:37])=O>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:35]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][N:29]=2)=[O:37])[CH:13]=1)[CH3:4]
Reactant: O=C(O)c1cnccn1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)c2cnccn2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and pyrazinecarboxylic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(pyrazine-2-carbonyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:32]4[CH:33]=[C:34]5[C:29]([CH:28]=[CH:27][NH:26]5)=[CH:30][CH:31]=4)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5cc[nH]c5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-6-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[S:10][C:11]([S:14]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18]3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)C=CC=CC=1.Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]([OH:52])([C:48]([F:51])([F:50])[F:49])[C:44]([F:47])([F:46])[F:45])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:8][C:9]1[S:10][C:11]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:37]3[N:38]=[CH:39][C:40]([C:43]([OH:52])([C:44]([F:45])([F:46])[F:47])[C:48]([F:50])([F:51])[F:49])=[CH:41][N:42]=3)[C@@H:19]([CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:18]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccc(N=C(c2ccccc2)c2ccccc2)s1)N1CCN[C@@H](CC2CCOCC2)C1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CC3CCOCC3)C2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
In a 20-mL vial was charged with N-(diphenylmethylidene)-5-(((3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)sulfonyl)-2-thiophenamine (170 mg, 0.334 mmol)), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (187 mg, 0.667 mmol, Intermediate D), and Hünig's base (175 μL, 1.001 mmol), and dioxane (5 mL). The vial was sealed and heated to 90° C. for 16 h. Afterwards, the mixture was concentrated in vacuo. The crude material was dissolved in THF (20 mL) and 4 N HCl in dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated, absorbed onto silica gel, and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (88 mg).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[C:17]1([CH3:29])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:25]([C:18]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[CH3:29])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)n2ncc3ccc(I)cc32)c(C)c1
Temperature: 23 °C
Yield: 100 %

Procedure:
To a solution of 6-iodo-1H-indazole (7.35 g, 30.1 mmol, 1 equiv) in THF (100 mL) cooled to 0° C. under argon, was added sodium t-butoxide (2.89 g, 30.1 mmol, 1 equiv). A color change from orange to red was observed. Mesitylenesulfonyl chloride (6.60 g, 30.1 mmol, 1 equiv) was added in one portion and the ice bath was removed allowing the reaction mixture to warm to 23° C. After 40 min the mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous was extracted a total of 3 times with ethyl acetate. The combined organic material was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 6-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as an orange solid (12.8 g, 100% yield, 2:1 mixture). 1H NMR (CDCl3) 8.51 (s, 1H), 7.95 (s, 0.66H, major isomer), 7.91 (s, 0.33H, minor isomer), 7.47 (d, 0.33H, J=8.4 Hz), 7.29 (d, 0.33H, J=8.4 Hz), 7.26 (d, 0.66H, J=8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.[H-].C([Al+]CC(C)C)C(C)C.O>C(Cl)Cl>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][CH:10]([N:11]2[CH2:12][CH2:13][CH2:14]2)[CH:5]([CH2:3][OH:2])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(CO)C1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (373 mg, 1.25 mmol) in anhydrous DCM (10 mL) was slowly added a solution of diisobutylaluminum hydride in hexanes (1M, 3.8 mL, 3.8 mmol) at −70° C. The reaction mixture was allowed to warm to −10° C. over 90 min, then stirred at RT for 15 min. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (188 mg, 88%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]1([NH:47][C:48](=[O:72])[C@H:49]([CH2:51][S:52][C:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH2:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:50][C@@H:49]([CH2:51][S:52][C:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]([NH:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:72])=[O:20])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)Nc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
456 mg (0.68 mmol) of the compound from example 2A was dissolved in 8 ml dichloromethane. 300 mg (0.68 mmol) N-Phenyl-S-trityl-L-cysteinamide, 0.12 ml (0.68 mmol) N,N-diisopropylethylamine and 260 mg (0.68 mmol) HATU were added. The reaction mixture was stirred at room temperature for 4 h. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified in two portions by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 361 mg (0.37 mmol, 53% of theory) of the desired product.
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:5]=1[C:18]([CH3:22])([CH3:21])[C:19]#N.C(O)(=[O:25])C>>[CH3:21][C:18]1([CH3:19])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:4]=2[O:3][C:22]1=[O:25]
Reactant: COc1c(Oc2ccccc2C)cccc1C(C)(C)C#N
Reactant: CC(=O)O
Agent: Cl
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2(C)C

Procedure:
Conc. hydrochloric acid (20 ml) and acetic acid (60 ml) were added to 2-[2-methoxy-3-(o-tolyloxy)phenyl]-2,2-dimethylacetonitrile (5.7 g), and the mixture was refluxed under heating for 48 hours. After cooling, the reaction mixture was evaporated. Saturated aqueous solution of sodium bicarbonate (100 ml) was added to the oily residue and warmed. After cooling, the mixture was extracted with ethyl acetate, and the extract was washed with water, dried and evaporated. The solid residue was purified by recrystallization from a mixture of ethanol and n-hexane to give 3,3-dimethyl-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.5 g). mp 115°-117° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCOC(=O)c1ncc[nH]1
Product: CCCCOC(=O)c1nccn1Cc1ccc2ccccc2c1
Yield: 69.9 %

Procedure:
5.0 g (29.7 mmol) of butyl imidazole-2-carboxylate and 6.6 g (29.7 mmol) of 2-bromomethylnaphthalene were reacted analogously to procedure 8a. 6.4 g (71%) of the product were obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH2:2][CH3:3].Cl>O1CCOCC1>[NH:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(=O)Nc1cccc(C2CCNCC2)c1
Yield: 99880.7 %

Procedure:
Into a stirred solution of tert-butyl 4-[3-(propionylamino)phenyl]-1-piperidinecarboxylate (18.8 g, 0.0543 mmol) in dioxane (100 mL) at 5° C. was bubbled HCl gas for 2 h. The solvent was removed in vacuo, the residue was dissolved in water (100 mL) and neutralized by adding 10% KOH aqueous solution. The aqueous layer was extracted (3×200 mL) with a mixture of CHCl3/isopropyl alcohol (3:1), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to afford the desired product (12.6 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.32 (d, 1H, J=7.2 Hz), 7.28–7.21 (m, 1H), 7.09 (s, 1H), 6.97 (d, 1H, J=7.6 Hz), 3.18 (d, 2H, J=12.6 Hz), 2.73 (dt, 2H, J=2.2, 11.2 Hz), 2.65–2.57 (m, 1H), 2.38 (q, 2H, J=7.4 Hz), 1.83 (d, 2H, J=12.1 Hz), 1.70–1.61 (m, 3H), 1.25 (t, 3H, J=7.5 Hz); ESMS m/e: 233.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH3:17][NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([CH3:35])[C:25]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=1)=[O:20]>>[CH3:17][NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([CH3:35])[C:25]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)[N:28]=1)=[O:20]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-4-methyl-thiophene-2-carboxylic acid methylamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 308c. Product isolated as a yellow foam (120 mg, 70%). LCMS (m/e) 501 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.08 (s, 1H), 7.23 (s, 1H), 7.09-7.05 (m, 2H), 6.93 (d, 1H, J=8.0 Hz), 6.81 (s, 1H), 5.98-5.91 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.96 (d, 3H, J=4.8 Hz), 2.90-2.85 (m, 2H), 2.82-2.66 (m, 8H), 2.13 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)sc2-c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Reaction time: 8 h

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (1.0 g) and methanesulfonyl chloride (0.27 ml) in pyridine (10 ml) was stirred overnight. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and treated with 4N sodium hydroxide (1.8 ml) for 2 hours. Ethyl acetate and water were added and the mixture was separated. The aqueous layer was acidified and extracted with ethyl acetate. The extract was dried and concentrated to dryness. The residue (1.1 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give a pale brown powder of N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}methanesulfonamide (0.79 g).
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].[CH3:15][C@:16]12[CH2:33][C:32](=[O:34])[C@H:31]3[C@@H:21]([CH2:22][CH2:23][CH:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:35])[CH2:25]4)[C@@H:20]1[CH2:19][CH2:18][C:17]2=[O:36]>C1COCC1.C(OCC)(=O)C>[OH:35][C@H:26]1[CH2:27][CH2:28][C@@:29]2([CH3:30])[CH:24]([CH2:23][CH2:22][C@@H:21]3[C@@H:31]2[C:32](=[O:34])[CH2:33][C@@:16]2([CH3:15])[C@H:20]3[CH2:19][CH2:18][C:17]2=[O:36])[CH2:25]1
Reactant: C[C@]12CCC(=O)CC1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
K SELECTRIDE® (potassium tri-sec-butylborohydride, 98.39 mL, 98.01 mmol, 1M solution in THF) is added to a solution of Compound 1.13 (33.0 g, 109.27 mmol) in THF (330 mL) over 15 minutes under an inert atmosphere at −78° C. and is stirred for about 3-4 h at −78° C. The reaction mixture is quenched with aqueous NaOH solution (2M, 70 mL). The crude reaction mixture is diluted with ethyl acetate (500 mL) and the organic layer is washed with water (3×75 mL), saturated brine solution (100 mL) and dried over MgSO4 (75 g). The solvent is removed under vacuum to afford 33 g of crude material. The crude product is subjected to acetylation without purification.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:4]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([Cl:9])[S:6][C:7]=1[Cl:8]>>[Br:2][C:3]1[C:4]([S:10]([NH2:1])(=[O:12])=[O:11])=[C:5]([Cl:9])[S:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Br
Reactant: N
Product: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Reaction time: 15 h

Procedure:
90 ml of an aqueous solution of NH3 (32%) is added at room temperature to a solution of 8.88 g of 4-bromo-2,5-dichloro-thiophene-3-sulfonylchloride in 120 ml of EtAc. The mixture obtained is stirred for ca. 15 hours. Two phases obtained are separated, the organic layer is washed with 1 N HCl and H2O, and dried. Solvent of the organic phase obtained is evaporated. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide is obtained in the form of a white powder. m.p. 113-117°; 13C—NMR (CDCl3): δ=108.287; 125.342; 130.404; 135.716.