Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:12]([C:10]1[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-7-yl}ethanone (95 mg, 0.33 mmol) and ammonium acetate (252 mg, 3.27 mmol) in methanol (1.8 mL) and acetonitrile (1.9 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (41.1 mg, 0.653 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with saturated sodium bicarbonate. The mixture was then extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (58 mg, 60%). The residue was used directly in the next step. LCMS calculated for C15H19ClN3O(M+H)+: m/z=292.1; found: 292.1.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 94 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (2-methoxyphenyl)boronic acid (49 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 40%, hexane-ethyl acetate) to give 76 mg (90% yield) of the title compound. Purity 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:24])[CH2:12][C@@H:13]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2].[CH2:25]=O>C1(C)C=CC=CC=1>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]=[C:8]([C@@H:11]2[O:24][CH2:25][N:17]([S:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])[CH:13]([CH:14]([CH3:15])[CH3:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc([C@H](O)C[C@@H](N[S@@](=O)C(C)(C)C)C(C)C)n1
Reactant: C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc([C@H]2CC(C(C)C)N(S(=O)C(C)(C)C)CO2)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 87.1 %

Procedure:
A 0.1 M solution of N-sulfinyl amino alcohol 32 (0.575 g, 1.53 mmol) in toluene (15.3 mL) with paraformaldehyde (0.917 g, 30.5 mmol) was heated in a sealed vessel at 70° C. with stirring for 50 h. After cooling to rt, the mixture was filtered through Celite, washing the filter cake thoroughly with toluene. The solution was concentrated and purified via HPFC (88:12 to 30:70 CH2Cl2:EtOAc) to afford 0.518 g of tetrahydrooxazine 33 (87%) as a foamy yellow solid. [α]25D=+108.4 (c=1.0, CHCl3). IR (film): 1011, 1076, 1087, 1163, 1195, 1474, 1729, 2957, 2979 cm−1. 1H NMR (500 MHz, CDCl3): δ 1.01 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz), 1.17 (s, 9H), 1.35 (t, 3H, J=7.1 Hz), 2.08-2.16 (m, 1H), 2.28-2.40 (m, 1H), 2.31 (d, 1H, J=14.3 Hz), 3.02 (dd, 1H, J=4.7, 10.1 Hz), 4.37 (q, 2H, J=7.1 Hz), 4.72 (d, 1H, J=11.6 Hz), 5.14 (d, 1H, J=11.6 Hz), 5.20 (dd, 1H, J=2.5, 11.5 Hz), 8.11 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 14.3, 20.5, 20.7, 22.8, 27.5, 32.6, 59.2, 61.3, 62.7, 71.4, 71.6, 127.8, 146.5, 161.3, 173.3. HRMS (FAB) calcd. for C17H29N2O4S2 (M+H): 389.1569. Found 389.1566.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:19]O.S(=O)(=O)(O)O>O>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)C(F)(F)F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C

Procedure:
2.33 g (8.56 mmol) of 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoic acid were introduced into 30 ml of methanol and admixed with 2 ml of concentrated sulfuric acid. The mixture was subsequently heated at reflux until a check by HPLC indicated full conversion. The contents were freed from the solvent, and the residue was taken up in water. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed once with saturated aqueous sodium hydrogen-carbonate solution. The organic phase was dried and freed from the solvent. The residue obtained was 2.1 g of clean product.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[NH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[C:12]([CH3:30])[N:11]=1.O.Cl>C1COCC1>[NH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([CH2:22][OH:23])=[CH:20][C:19]=2[O:28][CH3:29])=[C:12]([CH3:30])[N:11]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.6 %

Procedure:
Lithium triethylborohydride (93 mL) was added to a solution of the product from step (ii) (5.0 g) in THF (25 mL) over 5 min and the reaction mixture was stirred at RT for 3.5 h. Water (60 mL) and 2M-hydrogen chloride (40 mL) was added to the mixture. The organic solvent was removed by evaporation. 2M-hydrogen chloride (16 mL) was added and the mixture was stirred at RT for 4 h. The mixture was neutralized by saturated aqueous sodium hydrogen carbonate. The precipitate was collected by filtration, washed with water and dried in vacuo at 50° C. to afford the sub-title compound (4.7 g) as a white solid; 1H NMR (300 MHz, d6-DMSO); 10.76 (1H, br s), 6.89 (1H, s), 6.77-6.70 (2H, m), 6.30 (2H, br s), 5.10 (1H, t), 4.42 (2H, d), 3.79 (3H, s), 3.51 (2H, s), 1.91 (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])[C:15]2[C:20]([NH:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:25]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:26]
Reactant: [H][H]
Reactant: CCCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCNc1cccnc1N(CC)C1CCNCC1

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-propylamino-2-pyridinyl)amino]piperidine (EXAMPLE 191, 4.34 g, 12.3 mmol) and palladium hydroxide on carbon (2.0 g) in 50 ml ethanol is hydrogenated at 40 p.s.i. hydrogen for 40 hr. Filtration and removal of the solvent gives the title compound, NMR (400 MHz, CDCl3) 7.72, 6.95, 6.83, 3.72, 3.42, 3.09, 2.87, 2.00, 1.66, 1.24, 1.00 and 0.87δ.
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[CH2:12][CH2:11][N:10]1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.[Pt]=O>[ClH:1].[CH2:2]([CH:9]1[C:14]([CH3:16])([CH3:15])[CH:13]([OH:17])[CH2:12][CH2:11][N:10]1[CH3:18])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCC(=O)C(C)(C)C1Cc1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CN1CCC(O)C(C)(C)C1Cc1ccccc1
Yield: 98 %

Procedure:
A solution of 9 g of 2-benzyl-1,3,3-trimethyl-4-piperidone hydrochloride in 50 ml of methanol is submitted to catalytic hydrogenation at room temperature and atmospheric pressure, with 0.4 g platinum oxide as the catalyst. The product is crystallized from ethanol/ether. Yield 98%. Melting point, after recrystallization, 213°-222° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.CN(C)[CH:33]=[O:34]>>[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([CH:15]=1)[CH:33]=[O:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(C=O)cc2OCc2ccccc2)n1
Yield: 75.1 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 1.0 g, 2.66 mmol), MeLi (1.83 ml, 2.92 mmol), butyl lithium (1.17 ml, 2.92 mmol), and N,N-dimethylformamide (0.823 ml, 10.6 mmol) were reacted according to the method of Example 7 to provide the title compound (650 mg, 75.2% yield) as a pale yellow solid. 1H NMR (CDCl3) δ 9.91 (s, 1H), 8.88 (bs, 1H), 8.40 (d, 1H), 7.56 (d, 1H), 7.42 (m, 5H), 6.51 (m, 1H), 5.17 (s, 2H), 2.35 (s, 3H). Mass spectrum (apci) m/z=326.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH:16]([C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)[OH:17].C([BH3-])#N.[Na+]>>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH:16]([C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)[OH:17])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCOCc1ccccc1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(CCOCc1ccccc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 16 h

Procedure:
Combine 4-benzyloxy-2-butanone (2.6 g, 15 mmol) with 5-(2-amino-1-hydroxyethyl)salicylamide (15 mmol in methanol, 50 ml) and treat with sodium cyanoborohydride (0.9 g, 15 mmol). Let stand 16 hours, evaporate the solvent and extract the residue in ethyl acetate/ 1N sodium bicarbonate solution. Separate the organic phase, dry over sodium sulfate and evaporate in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([CH3:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1.ClC(Cl)(Cl)C#N>C(#N)C>[CH3:9][N:10]([CH3:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]2[O:8][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Nc1cccnc1O
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(C)c1ccc(-c2nc3cccnc3o2)cc1
Temperature: 150 °C
Yield: 6.7 %

Procedure:
3-Amino-pyridin-2-ol (50 mg, 0.45 mmol), 4-dimethylamino-benzoic acid (74 mg, 0.45 mmol), trichloroacetonitrile (91 μL, 0.91 mmol), and polystyrene triphenylphosphine (425 mg, 1.362 mmol) were suspended in acetonitrile (4.5 mL) and heated by microwave to 150° C. for 15 min. The crude reaction mixture was filtered and concentrated affording a residue which was purified by reverse phase chromatography affording dimethyl-(4-oxazolo[5,4-b]pyridin-2-yl-phenyl)-amine (7.1 mg, 0.030 mmol, 6.6% yield). ES MS (M+H+)=240; 1H NMR (300 MHz, CDCl3): δ 8.24 (d, J=5.1 Hz, 1H); 8.14 (d, J=8.6 Hz, 2H); 7.95 (d, J=7.8 Hz, 1H); 7.28 (dd, J=7.7, 4.9 Hz, 2H); 6.78 (d, J=8.6 Hz, 1H); 3.09 (s, 6H); HRMS m/z 240.1122 (C14H13N3O1+H+ requires 240.1132).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:19]=1)=[CH:8][CH:9]=[C:10]1[C:14]=2[N:13]([CH2:15][CH:16]([NH2:18])[CH3:17])[N:12]=[CH:11]1.[B-](Br)(Br)(Br)[S+](C)C.C([O-])(O)=O.[Na+]>ClCCCl>[NH2:18][CH:16]([CH3:17])[CH2:15][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]3[CH:19]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]3=2)[CH:11]=[N:12]1
Reactant: COc1ccc2c(ccc3cnn(CC(C)N)c32)c1
Agent: C[S+](C)[B-](Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(N)Cn1ncc2ccc3cc(O)ccc3c21
Yield: 33.2 %

Procedure:
To a solution of the product from Step D (26 mg, 0.1 mmol) in 1,2-dichloroethane (10 mL) was added boron tribromide-methylsulfide complex (1.0 M, 1.0 mL, 1.0 mmol) and the solution stirred at reflux for 72 h. The solution was poured into aqueous NaHCO3, and extracted with ethyl acetate (2×20 mL). The combined extracts were dried (MgSO4) concentrated to a residue, which was purified by chromatography (silica, gradient, 10 to 25% methanol in dichloromethane) to furnish a solid (8 mg, 32%): 1H NMR (CDCl3) δ 8.30 (d, J=9.0 Hz, 1H), 7.99 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.21 (dd, J=9.0, 2.4 Hz, 1H), 3.6 (m, 1H), 3.3 (m, 2H), 1.25 (d, J=6.6 Hz, 3H); MS m/z 242 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.N1CCCCC1>C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1
Temperature: 105 °C

Procedure:
A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (13.86 g, 138.4 mmol), 4-methoxy thiophenol (20.0 g, 138.4 mmol), and piperidine (3.45 g, 41.6 mmol). This mixture was heated to 105° C. for 32 hours, cooled to room temperature and dissolved in ethyl acetate (EtOAc) (700mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded an oil which, upon standing in the freezer, provided a crystalline solid. 3-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid was isolated as pale-yellow crystals by washing the crystalline solid with pentane. (27.33 g, 82%). 1H NMR (300 MHz, CDCl3) δ: 7.48 (2H, d, J=9.0 Hz), 6.89 (2H, d, J=8.9 Hz), 3.83 (3H, s), 2.54 (2H, s), 1.40 (6H, s).
Reaction SMILES: N(C(OC)=O)=NC(OC)=O.COC1C=CC2N(C)C3C(SC=2C=1CO)=C(COCOCCOC)C(OC)=CC=3.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)C.CCCCCC.C(OCC)(=O)C>[C:43]1(=[O:45])[C:42]2[CH:41]([CH2:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[NH:44]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: COC(=O)N=NC(=O)OC
Agent: COCCOCOCc1c(OC)ccc2c1Sc1c(ccc(OC)c1CO)N2C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C2CC=CC=C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3.19 g (18.32 mmol) of dimethyl azodicarboxylate in 10 ml of tetrahydrofuran was added within 4 hours under argon and while cooling with ice to a solution of 6.44 g (15.24 mmol) of [3,7-dimethoxy-6-(2-methoxy-ethoxymethoxymethyl)-10-methyl-phenothiazin-4-yl]-methanol, 2.68 g (18.11 mmol) of phthalimide and 4.40 g (16.77 mmol) of triphenylphosphine in 75 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for a further 2 hours, brought slowly to room temperature and then poured into ice-water and ethyl acetate. The mixture was treated with hexane and ethanol, whereupon it was shaken vigorously. The organic phase was separated, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and evaporated, and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:1). After recrystallization from methanol 6.83 g (81.2%) of 2-[3,7-dimethoxy-6-(2-methoxy-ethoxymethoxymethyl)-10-methyl-phenothiazin-4-ylmethyl]-2,3:-dihydro-1H-isoindole-1,3-dione were obtained as a white solid of m.p. 135°-137°.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=[O:3])[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[C:1]([CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[CH2:29][CH2:28]1)(=[O:3])[NH2:2]
Reactant: NC(=O)Cc1ccccc1OCC1CO1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2CC(N)=O)CC1

Procedure:
A solution consisting of 5.0 g. of 1-(2-carbamoylmethylphenoxy)-2,3-epoxypropane and 4.6 g. of 1-(2-methoxyphenyl)piperazine dissolved in 50 ml. of ethanol was allowed to stand at room temperature (~25°C.) for a period of approximately 16 hours. At the end of this time, the resultant precipitate was removed from the reaction mixture by means of suction filtration and subsequently recrystallized from ethyl acetate to give 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol as the pure free base compound, m.p. 120°-122°C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([O:13][C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=1>COCCOC.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>[Cl:30][C:28]1[CH:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Reactant: Nc1ncc(Cl)cc1Br
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: O
Solvent: COCCOC
Product: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
A mixture of sodium carbonate (307 mg), tetrakis(triphenylphosphine)palladium(0) (50.1 mg), 4-(cyclohexyloxy)phenylboronic acid (414 mg) and 3-bromo-5-chloropyridin-2-amine (300 mg) in DME (15 mL) and water (3 mL) was stirred at 80° C. for 5 hr. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (212 mg) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25](O)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:65][C:66]([F:70])([F:69])[CH2:67][NH2:68]>CN(C=O)C>[F:65][C:66]([F:70])([F:69])[CH2:67][NH:68][C:25]([CH:23]1[CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH2:11][C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=4)([C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:16][CH:17]=2)[CH2:24]1)=[O:26]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added DIPEA (0.052 g, 0.406 mmol), HOBt (0.027 g, 0.203 mmol), EDCl.HCl (0.058 g, 0.304 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.027 g, 0.203 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), dried over sodium sulphate and evaporated in vacuo to get 0.170 mg crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford pale yellow solid, which was re-purified by DCM in pentane (1:9) to afford pale yellow solid (0.082 g, 71%). 1H-NMR (400 MHz, CDCl3) δ: 3.43-3.48 (m, 1H), 3.62 (d, 1H, J=17.04), 3.93-4.00 (m, 2H), 4.04 (d, 1H, J=17.0), 4.09-4.14 (m, 4H), 5.94 (t, 1H, J=6.06 Hz), 6.43 (d, 2H, J=8.72 Hz), 7.47-7.50 (m, 2H), 7.63 (s, 2H); LC-MS (m/z): [M−H] 571.70.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)[N:9]=3)[CH:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.6) (0.43 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.46 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCCCCC(=O)O)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
Part B. The ester prepared in Part A above (14.4 g, 32.6 mmol) was stirred in ethanolic sodium hydroxide (240 mL, 0.25N, 60 mmol, about 5% water added) at ambient temperature for 48 hours. The reaction mixture was evaporated, neutralized to pH 7 with small portions of 1N aqueous hydrochloric acid, and saturated with sodium chloride. This mixture was extracted with ethyl acetate (2×200 mL), and the extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 5-[4,5-bis(4-methoxyphenyl)-1H-imidazole-2-ylthio]pentanoic acid as a waxy solid (12.1 g, 29.3 mmol, 90%).
Reaction SMILES: C([O-])(=O)COCC([O-])=O.[Zn+2:10].[C:11]([OH:25])(=[O:24])[CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22].C(O)(=O)COCC(O)=O.O.[OH-].[Zn+2].[OH-]>>[C:21]([O-:23])(=[O:22])[CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O-:25])=[O:24].[Zn+2:10]
Reactant: O=C(O)COCCOCCOCC(=O)O
Agent: O=C(O)COCC(=O)O
Agent: O=C([O-])COCC(=O)[O-]
Agent: [OH-]
Solvent: O
Product: O=C([O-])COCCOCCOCC(=O)[O-]

Procedure:
Zinc 3,6,9-trioxaundecanedioate was prepared by essentially the procedure described above for zinc diglycolate, with the exception that 3,6,9-trioxaundecanedioic acid (23.86 g, 0.107 mole) was substituted for the diglycolic acid and was added directly to the water/zinc hydroxide slurry.