Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2.[C:29](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:29])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A mixture of ethyl 5-(2-methoxyethoxy)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.50 g), potassium carbonate (480 mg) and N,N-dimethylformamide (20 mL) was stirred at 0° C. for 30 min. Methyl iodide (550 mg) was added at 0° C. to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-hexane (4:1-2:1) to give the title compound (1.30 g, yield 85%) as a colorless 25 oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:18])=[O:14])[CH:10]=[CH:11][CH:12]=1)[NH2:5])#[N:2]>CO.C1COCC1.[OH-].[Na+]>[NH2:5][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH:20]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[O:14])[CH:10]=[CH:11][CH:12]=1)=[N:3][C:1]#[N:2]
Reactant: N#CN=C(N)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)OCc2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CN=C(N)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a stirred solution of the compound from Example 134 (285 mg) in methanol (3 ml) and THF (3 ml), 1N sodium hydroxide (3 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, evaporated and the residue dissolved in water. The resulting solution was adjusted to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate/MeOH. The organic extracts were washed with water, dried (Na2SO4) and evaporated to afford an off white solid. The crude product was further purified by reverse phase HPLC on a C18 column (eluant:0.5% TFA-water/acetonitrile) and lyophilized to afford the title compound (65 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)[C:26]([C:28](O)=[O:29])=[CH:27][C:20]=2[N:19]=1.[NH2:41][C:42]1[O:46][N:45]=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=1.ClC(N(C)C)=C(C)C>C1COCC1>[C:47]([C:44]1[CH:43]=[C:42]([NH:41][C:28]([C:26]2[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:39])([F:38])[F:40])[CH2:33][CH2:32]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:29])[O:46][N:45]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3cc(C(C)(C)C)no3)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound is prepared in analogy to 1b from 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (100 mg, 0.16 mmol), 5-amino-3-tert.-butyl-isoxazole (23 mg, 0.16 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.026 mL, 0.20 mmol) TEA (0.114 mL, 0.81 mmol) and THF.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[NH:8][C:9](=O)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]([C:18]3[C:23]([Br:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=3[Br:29])[C:11]=2[N:12]=1>O>[Cl:3][C:9]1[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]([C:18]3[C:23]([Br:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=3[Br:29])[C:11]=2[N:12]=[C:7]([CH3:6])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(C)c(C)n2-c2c(Br)cc(C(F)(F)F)cc2Br)c(=O)[nH]1
Solvent: O
Product: Cc1nc(Cl)c2c(C)c(C)n(-c3c(Br)cc(C(F)(F)F)cc3Br)c2n1
Temperature: 100 °C

Procedure:
2, Phosphorus oxychoride in an amount of 1.3 ml was added to 0.67 g of 2,5,6-trimethyl-7-(2,6-dibromo-4-trifluoromethylphenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, and the reaction mixture was heated for 0.5 hours at 100° C. and was then cooled. The reaction mixture was poured into water with ice and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and was allowed to stand for crystallization to yield 0.66 g of 4-chloro-2,5,6-trimethyl-7-(2,6-dibromo-4-trifluoromethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [OH:1][C@H:2]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:3][NH:4][C@H:5]([CH3:16])[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.C(N(CC)CC)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH3:4].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([CH2:6][C@H:5]([NH:4][CH2:3][C@H:2]([OH:1])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=3)[CH3:16])[CH:8]=2)=[CH:36][CH:35]=1
Reactant: C[C@H](Cc1cccc(C(=O)O)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Reactant: NCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Cc1cccc(C(=O)NCc2ccc(Cl)cc2)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 153.2 %

Procedure:
To a solution of 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) (120 mg, 0.27 mmol) in DMF (3 ml) was added triethylamine (111 μl, 0.79 mmol), 4-chlorobenzylamine (39 μl, 0.32 mmol), and HBTU (110 mg, 0.29 mmol) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (93:7:0.7 changing to 90:10:1, by volume) to give the title compound as a white foam (97 mg). 1H NMR (400 MHz, CD3OD): δ=7.70-7.68 (1H, d), 7.66 (1H, s), 7.38-7.30 (6H, m), 7.23 (1H, d), 7.05-7.03 (1H, dd), 6.70-6.68 (1H, d), 4.67-4.64 (1H, dd), 4.62 (2H, s), 4.55 (2H, s), 3.15-3.07 (1H, m), 3.00-2.86 (2H, m), 2.82-2.78 (1H, dd), 2.72-2.67 (1H, dd), 1.13-1.12 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 469, [M+Na]+ 491, [M−H]− 467.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:20][CH:19]=4)[N:15](COCC[Si](C)(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])=[CH:22][CH:23]=4)[NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42]
Reactant: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3[nH]2)cc1
Reaction time: 3 h
Yield: 68.4 %

Procedure:
1-{2-Chloro-4-[6-[4-(2-diethylaminoethoxy)-phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea (40 mg, 0.0601 mmol) was dissolved in 1 ml of tetrahydrofuran, and then 0.5 ml (8.3 equivalents) of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added dropwise and the mixture was refluxed for 2 hours. After returning to room temperature, 3 ml of water was added, the mixture was allowed to stand for 3 hours, and the precipitating crystals were filtered out, washed with water and ether:hexane=1:1 and dried under reduced pressure to obtain 22 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:12]([NH2:26])=[N:13][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[O:18][CH2:17][CH2:16]2)[N:15]=1>>[NH2:26][C:12]1[C:11]([CH3:10])=[N:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:9])[CH:23]=3)[O:18][CH2:17][CH2:16]2)[N:13]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC1=NC2(CCOc3ccc(N)cc32)N=C1N
Product: CC1=NC2(CCOc3ccc(NC(=O)c4ccc(C)s4)cc32)N=C1N
Yield: 55.8 %

Procedure:
The title compound (45.5 mg, 57% yield) was prepared as described or Example 13a starting from 5-methylthiophene-2-carboxylic acid (32.1 mg, 0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 52 mg, 0.23 mmol): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.91 (m, 2 H), 2.23 (s, 3 H), 2.47 (s, 3 H), 4.39 (m, 2 H), 6.55 (s, 2 H), 6.73 (d, 1 H), 6.78 (d, 1 H), 6.86 (dd, 1 H), 7.50 (dd, 1 H), 7.73 (d, 1 H), 9.86 (s, 1 H); MS (ES+) m/z 355 [M+H]+.
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].Cl.Cl.[NH2:39][CH2:40][C@H:41](N1CCCCC1)[C:42]([O:44][CH3:45])=[O:43].C(N(CC)CC)C>CN(C)C=O>[CH2:23]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:39][CH2:40][C@H:41]([CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:42]([O:44][CH3:45])=[O:43])=[O:34])=[CH:35][CH:36]=1)[C:24]#[C:25][CH3:26]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](CN)N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
420 mg (3.1 mmol) of 1-hydroxybenzotriazole and 600 mg (3.1 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride are added to a solution of 540 mg (3.1 mmol) of 4-but-2-ynyloxybenzoic acid in 10 ml of dimethylformamide. The reaction medium is stirred for 15 min at ambient temperature then 630 mg (2.8 mmol) of methyl (S)-3-amino-2-piperidin-1-yl-propanoate dihydrochloride in 10 ml of dimethylformamide and 0.8 ml (5.7 mmol) of triethylamine are added. The reaction medium is stirred at ambient temperature for 18 h. The organic phase is washed with an aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude product obtained is purified by chromatography over silica gel eluted with a 99/1 dichloromethane/methanol mixture. 580 mg (58%) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-cyclohexylpropanoate are obtained in the form of a colourless oil.
Reaction SMILES: Cl.N[C@H]1CCCC[C@H]1CNCCO.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([O:48]CC2C=CC=CC=2)=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH:39]([CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH:32]3[CH2:31][N:30]2[CH:47]=1)[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:25]>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([OH:48])=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH:39]([CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH:32]3[CH2:31][N:30]2[CH:47]=1)[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:25]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C3CCCCC3CN(CCO)C1C2
Agent: Cl
Agent: N[C@H]1CCCC[C@H]1CNCCO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C3CCCCC3CN(CCO)C1C2

Procedure:
In a manner similar to that described in example Z-35, from 16a (45 mg, 0.0957 mmol) and racemic-2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanol hydrochloride (102 mg, 0.418 mmol) was prepared racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2a]quinazoline-10-carboxamide (7 mg, 12%) as a white solid after silica gel chromatography (1-12% methanol/dichloromethane gradient elution). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a, 5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (7 mg, 0.0118 mmol) the title compound was prepared after purification by HPLC (3 mg, 50%), 1H NMR (CDCl3) 12.57 (br s, 1H), 10.45 (m, 1H), 8.29 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.80 (m, 1H), 4.71 (s, 1H), 4.62 (m, 2H), 4.44 (m, 1H), 4.33 (m, 1H), 3.75 (m, 1H), 3.62-3.20 (m, 3H), 3.13 (m, 1H), 2.74-2.71 (m, 2H), 2.24 (m, 1H), 1.90-137 (m, 12H), 1.27-1.23 (m, 3H) 1.12 (m, 1H); ES+ MS: 503 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1)=[O:30]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1sccc1Cl
Reaction time: 4 h
Yield: 41.5 %

Procedure:
The intermediate 5-chloro-2-(1H-tetrazol-5-yl)aniline (200 mg, 1.0 mmol) and diisopropylethylamine (310 uL, 1.7 mmol) were taken up in 5 mL of dichloromethane. To the solution was added 3-chlorothiophene-2-carboyl chloride (221 mg, 1.2 mmol). The solution was stirred for 4 hours, at which point starting material was no longer detected by LCMS analysis. Dichloromethane (10 ml) was then added to solution. This solution was extracted 3 times with an aqueous solution of 0.1 N NaOH. The aqueous extractions were combined and concentrated HCl was added to until pH=1. The resulting precipitate was filtered and washed with acetonitrile to yield final product (141.1 mg, 41%). 1H NMR (400 MHz, d6-DMSO): 11.89 (s, 1H), 8.60 (s, 1H), 8.26 (d, 1H), 8.05 (d, 1H), 7.45 (d, 1H), 7.30 (d, 1H). MS (EI) for C12H7Cl2N5OS: 340.2 (M+H).
Reaction SMILES: C(N[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:16]([CH:19]=1)[C:17]#[N:18])(=[O:11])=[O:10])C1C=CC=CC=1.[ClH:33].Cl[O-].[Na+]>ClCCl>[C:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:15]1[CH:14]=[CH:13][C:12]([S:9]([Cl:33])(=[O:11])=[O:10])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1cc(S(=O)(=O)NCc2ccccc2)ccc1Oc1ccccc1-c1ccccc1
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1

Procedure:
A mixture of 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile (Preparation 56, 6.06 g, 15.4 mmol), dichloromethane and aq HCl was stirred vigorously with cooling (ice bath). Sodium hypochlorite was added dropwise over 30 minutes and stirring continued with cooling for 1 hour. The layers were separated, the aqueous extracted with dichloromethane (2×100ml), and the organic collected, dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Heptane 10/90 to 20/80) to furnish 4.58 g of the title compound. 1HNMR (CDCl3): δ 6.7 (m, 1H), 7.2-7.6 (m, 9H), 7.85 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: N1C(C)=CC=CC=1C.[CH3:9][N:10]1[C@@H:14]([CH3:15])[C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][C:11]1=[O:22].Br[CH2:24][C:25](Br)=[O:26].C(=O)(O)[O-].[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][C:53]=1[Cl:54])[O:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40][CH2:39]1>O1CCCC1.O>[Cl:33][C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][C:53]=1[Cl:54])[O:37][CH:38]1[CH2:39][CH2:40][N:41]([CH2:44][CH:45]2[CH2:46][CH2:47][N:48]([CH2:24][C:25]([N:12]3[C@H:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@H:14]([CH3:15])[N:10]([CH3:9])[C:11]3=[O:22])=[O:26])[CH2:49][CH2:50]2)[CH2:42][CH2:43]1
Reactant: O=C(Br)CBr
Reactant: C[C@H]1[C@@H](c2ccccc2)NC(=O)N1C
Reactant: Clc1ccc(OC2CCN(CC3CCNCC3)CC2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)CN2CCC(CN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)CC2)C(=O)N1C
Reaction time: 0.25 h

Procedure:
2,6Lutidine (18.26 mL) was added to a stirred suspension of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one (27.33 g) in anhydrous tetrahydrofuran (300 mL) at 0° C. under nitrogen. Bromoacetyl bromide (11.95 mL) was added over 5 minutes and the mixture was stirred for a further 15 minutes. Saturated aqueous sodium bicarbonate solution (300 mL) was added followed by 4-(3,4-dichlorophenoxy)-1-(4-piperidinylmethyl)piperidine (44.86 g) and the mixture was stirred for 24 hours at ambient temperature. Water (300 mL) was added and the mixture was extracted with tert-butyl methyl ether (300 mL). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was suspended in tert-butyl methyl ether (300 mL) and stirred for 3 days. The resulting solid was filtered, washed with tert-butyl methyl ether (3×50 mL) and dried in under reduced pressure to give the title compound (45.65 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:12])[CH:6]=1)[CH3:2].C1COCC1.C1(O)C=CC=CC=1.[I:26]I>C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([I:26])[C:8]([OH:11])=[C:7]([Br:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(Br)c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(O)c(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a mixture of 3-bromo-4-hydroxybenzoic acid ethyl ester (69.2 g, 282 mmol) in 2N aqueous potassium carbonate (423 mL) was added sufficient THF to completely dissolve the phenol and make the solution clear (˜300 to 500 mL). The solution was cooled to 0° C. and I2 (158 g, 621 mmol) was added portionwise at such a rate as not to accumulate a large amount of solid I2 on the bottom of the flask. After addition was complete, the ice bath was removed, and the solution was allowed to warm to room temperature. The reaction was complete in 2 h. Worked up by adding (slowly with caution) solid sodium bisulfite at a rate so excess foaming doesn't occur. Sodium bisulfite was added until nearly decolorized. The mixture was acidified with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layers combined, washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give 3-bromo-4-hydroxy-5-iodobenzoic acid ethyl ester (94.6 g, 90%) as a pale yellow solid. NMR indicated it was suitable for use in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=6.8 Hz, 3H, —CO2CH2CH3), 4.32 (t, J=6.8 Hz, 2H, —CO2CH2CH3), 8.14 (d, 1H, arom), 8.32 (d, 1H, arom).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12]CC)=O)[CH:5]=1.[CH3:15][C:16]([CH3:18])=[O:17].[ClH:19]>O1CCCC1.O>[Cl:19][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](=[O:12])[CH2:15][C:16](=[O:17])[CH2:18][C:10]([C:6]2[CH:5]=[C:4]([Cl:3])[CH:9]=[CH:8][N:7]=2)=[O:12])[CH:5]=1
Reactant: Cl
Reactant: CCOC(=O)c1cc(Cl)ccn1
Reactant: CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cc(Cl)ccn1)CC(=O)c1cc(Cl)ccn1

Procedure:
4 g (0.1 mol. about 60% dispersion) of sodium hydride in 100 ml of absolute tetrahydrofuran are placed in a reaction vessel under a nitrogen atmosphere. At <56° C., a solution of 18.5 g (0.1 mol) of ethyl 4-chloropyridine-2-carboxylate and 2.32 g (0.04 mol) of dried acetone in 75 ml of THF is added dropwise over the course of two hours. The red suspension is then carefully poured into 900 ml of water. It is rendered neutral with 6N HCl, tetrahydrofuran is distilled off on a rotary evaporator, and the yellow to beige 1,5-bis(4-chloropyridin-2-yl)pentane-1,3,5-trione formed is filtered off. The dried, sparingly soluble product is processed further without any particular purification steps. IR (cm−1): 1619 (m); 1564 (s); 1546 (s); 1440 (m); 1374 (s); 1156 (m); 822 (w).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([O:23][C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[CH:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C>C1COCC1.O>[Si:1]([O:8][C@H:9]1[CH2:10][C@H:11]([O:23][C:24]2[CH:25]=[C:26]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[N:27]=[CH:28][N:29]=2)[CH2:12][C@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Yield: 77.7 %

Procedure:
A solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine (0.32 g, 0.00053 mol) in THF (2.88 mL), water (2.88 mL), and acetic acid (8.64 mL) was stirred for 3 days. The reaction was concentrated and azeotroped 2× with toluene. The residue was purified by flash chromatography (30 to 80% EtOAc/hexanes) give 0.20 g (77%) of the title compound. LC/MS: Rt=1.59 min, ES+ 486 (FA standard).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(OCC)(=O)C.CCCCCCC>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 25 °C

Procedure:
At 120° C., 31 g (123 mmol) of p-fluorobenzamide and 33 g (123 mmol) of 1,3-dichloroacetone were stirred in the absence of a solvent for 2 hours. After cooling to room temperature, the product was dissolved in 250 ml of ethyl acetate. This solution was diluted with 400 ml of n-heptane and washed 3 times with saturated NaCl solution. The organic phase was filtered through 250 ml of silica gel, and the filter pad was then washed with 200 ml of n-heptane/ethyl acetate (4:1). The solvent was distilled off, giving 4-chloromethyl-2-(4-fluorophenyl)oxazole 1 as crude product. This was dissolved in 650 ml of acetone, and 90 g of NaI were then added. The mixture was then heated at reflux for 16 hours, most of the solvent was then removed and the solid residue was suspended in 200 ml of n-heptane/ethyl acetate (1:1) and filtered through 200 ml of silica gel. The precipitate was washed with 500 ml of n-heptane/ethyl acetate (1:1), and the organic phase was concentrated. On concentration, the iodide 2 began to crystallize as white crystals. TLC n-heptane/ethyl acetate (6:1) Rf 0.4 for 2 and Rf=0.35 for 1. C10H7FINO (303.08) MS(ESI): 304 (M+H+).