Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1>>[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:5][CH2:6][NH:7][C:3](=[O:4])[CH2:1][CH3:2])=[CH:15][CH:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: CCC1=NCCO1
Product: CCC(=O)NCCOc1ccc(-n2ccnc2)cc1

Procedure:
To 25 g (0.25 mol) of 2-ethyl-4,5-dihydrooxazole add 10.0 g (62 mmol) of 4-(1H-imidazol-1-yl)phenol. Reflux the reaction mixture. Monitor the progress of the reaction by thin-layer chromatography on silica gel (9:1, CH2Cl2 :MeOH). Upon completion of the reaction remove the excess starting material by distillation, add ethyl acetate, and wash the solution with 2 N NaOH. Dry the organic layer over anhydrous Na2SO4. Remove the drying agent by filtration and remove the solvent in vacuo. Recrystallization from ethyl acetate-hexane affords the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]1=[O:25])(C(C)(C)C)(C)C.Cl>O1CCOCC1>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CNCCN1CCCO
Reaction time: 4 h
Yield: 57.4 %

Procedure:
Tert-butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-oxopiperazine-1-carboxylate (2.90 g, 7.8 mmol) in 1,4-dioxane (10 ml) was treated at room temperature with a 4N solution of HCl in 1,4-dioxane (15 ml) and the resulting solution stirred 4 hr then evaporated. The residue was taken up in a 10% methanol in dichloromethane solution (30 ml) and basified with a 7N solution of ammonia in methanol then filtered and the filtrate evaporated. The residue was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent to give 1-(3-hydroxypropyl)piperazin-2-one (708 mg, 57%) as a colourless oil; NMR Soectrum:(CDCl3) 1.77 (quintet, 2H), 2.72 (s(br), 2H), 3.09 (t, 2H), 3.32 (t, 2H), 3.55 (m, 6H).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[Br:22]>CO.C(Cl)(Cl)Cl>[Br:22][C:17]1[C:18]([CH3:21])=[N:19][O:20][C:16]=1[NH:15][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)s1
Reactant: Cc1noc(N)c1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccs3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5,2'-bithiophene (300 mg, 1.14 mmol) with 5-amino-4-bromo-3-methylisoxazole (183 mg, 1.03 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3, 430 mg (94%) of a pale brown solid, m.p. 210° C.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH2:35][CH3:36])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(Cl)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)cc1

Procedure:
4-Amino-5-chloro-N-((1-(5-(4-chlorobenzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.8 g) as starting compound, acetaldehyde (0.26 ml) and sodium cyanoborohydride (0.29 g) were reacted and treated in the same manner as in Example 136 to give 1.05 g of 4-amino-5-chloro-N-((1-(5-(N-(4-chlorobenzyl)-N-ethylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(OC([N:8]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])[CH2:46][CH2:45]2)(=[O:43])=[O:42])(=[O:34])=[O:33])[CH:25]=1)[C:9]([NH:11]C(OC(C)(C)C)=O)=[NH:10])=O)(C)(C)C.[ClH:58].CO.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:58].[CH3:30][C:28]1[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]2[CH2:45][CH2:46][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])[CH2:48][CH2:49]2)(=[O:42])=[O:43])(=[O:33])=[O:34])[CH:25]=[C:24]([CH:29]=1)[O:23][CH2:22][CH2:21][CH2:20][O:19][NH:8][C:9]([NH2:11])=[NH:10]
Reactant: COc1ccccc1N1CCN(S(=O)(=O)c2ccccc2S(=O)(=O)Oc2cc(C)cc(OCCCON(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Solvent: CO
Product: COc1ccccc1N1CCN(S(=O)(=O)c2ccccc2S(=O)(=O)Oc2cc(C)cc(OCCCONC(=N)N)c2)CC1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from N,N′-bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine, as prepared in the previous step, in a manner analogous to step i of Example 20 (without HCl-methanol acidification). 1H NMR (300 MHz, CDCl3) δ8.21 (m, 2H), 7.81 (t, 1H, J=7.5 Hz), 7.69 (t, 1H, J=7.5 Hz), 7.00 (m, 1H), 6.89 (m, 3H), 6.58 (s, 2H), 6.53 (s, 1H), 3.95 (m, 4H), 3.82 (s, 3H), 3.53 (m, 4H), 3.11 (m, 4H), 2.22 (s, 3H), 2.03 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C28H35N5O8S2: 634.2 (M+H), 656.2 (M+Na). Found: 634.2, 656.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:38]([O:37][C:35]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4[nH]3)c(OC)cc2OC)cc1
Yield: 0.9 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 3.0 g, 6.5 mmol) in 250 mL of acetone were added ethyl chloroformate (0.93 g, 8.6 mmol) and K2CO3 (2.3 g, 16.7 mmol). The mixture was heated to reflux overnight. The yellow precipitate-formed was filtered. The filtrate was acidified to pH=1 with 3N HCl and extracted with CH2Cl2. The organic phase was washed with water, dried over MgSO4, and concentrated. The residue was further purified by passing a short silica gel column eluted with EtOAc/hexenes (1:1) to give 30 mg of the title compound as a yellow solid, mp 165–175° C. 1H-NMR (300 MHz, CDCl3) δ 9.39 (br, 1H), 8.04–8.20 (m, 6H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.12–7.07(m, 2H), 6.87 (s, 1H), 6.59 (s, 1H), 4.16 (q, J=7 Hz, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:30]=[CH:29]3)[C@@H:9]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH2:10][O:11]CC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[N:30]=[CH:29]3)[C@@H:9]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCC(=O)N[C@@H](CO)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(1S)-2-(3-Fluorophenyl)-2-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}-1-(benzyloxymethyl)ethyl]-2-methoxyacetamide (15 mg, 0.027 mmol) is dissolved in 10 mL ethanol and Pd (10% on charcoal, 0.29 mg, 0.0027 mmol) is added. The reaction mixture is charged with hydrogen and stirred for 2 h at r.t. After filtration of the reaction mixture via a glass microfibre filter, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethylacetate/hexane). 7.5 mg (59.6%) of the title compound as a mixture of stereoisomers are obtained.
Reaction SMILES: [Si]([O:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])(C)(C)C.[Br-].[Li+:14].CC([N-]C(C)C)C.C1COCC1>C(Cl)Cl>[O:5]([S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])[Li:14]
Reactant: [Li+]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: [Li]OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Me3SiOTf (0.90 ml, 5.0 mmol ) was added at −78° C. to a solution of iminiun bromide 3f (1.83 g, 5.0 mmol) in CH2Cl2 (30 ml). The suspension was warmed to room temperature and stirred for 1 hour. After evaporation of the solvent, a solid residue was obtained. Then to a 1/1 mixture of LDA and iminium triflate (5.0 mmol), 30 ml of THF was added at −78° C. The suspension was warmed to room temperature and stirred for 30 min. After evaporation of the solvent under vacuum, a solid residue containing carbene Cf and LiOTf was obtained. 1H NMR (thf-d8, 25° C.): 7.00-7.20 (m, 3H, Har), 3.34 (m, 1H, CHCH3), 2.85 (sept, 2H, CHCH3, J=6.9), 1.85-1.96 (m, 1H, CH2), 1.29-1.62 (m, 3H, CH2), 1.18 (d, 3H, CHCH3, J=6.9), 1.14 (d, 3H, CHCH3, J=6.9), 1.11 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.00 (d, 3H, CHCH3, J=6.6), 0.98 (d, 3H, CHCH3, J=6.3), 0.94 (d, 3H, CHCH3, J=6.3). 13C NMR (thf-d8, 25° C.): 322.00 (C), 144.45 (Car), 144.02 (Car), 142.35 (Car), 126.86 (Car), 123.44 (Car), 123.37 (Car), 56.15 (CH), 41.88 (C), 28.39, 28.26, 27.95, 27.12 (CH2), 26.88 (CH2), 26.47, 24.64, 23.91, 22.21, 21.70, 18.34.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][C:28]([CH3:33])=[CH:29]B(O)O.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]([CH:27]=[C:28]([CH3:33])[CH3:29])[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CC(C)=CB(O)O
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(C=C(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (2-methylprop-1-en-1-yl)boronic acid (1.00 g), triethylamine (2.00 mL), pyridine (1.00 mL) and molecular sieves 4 A (2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.00 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.080 g, 7%).
Reaction SMILES: [C:1]12([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4](=O)[CH2:3][CH2:2]2.O.NN.[OH-].[K+]>C(O)CO>[C:1]12([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CCC2(CC1)CCC(=O)c1ccccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C1CCC2(CCCc3ccccc32)CC1
Reaction time: 18 h
Yield: 69.5 %

Procedure:
A solution of 3.63 g. (0.0115 M) of spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal(p) (prepared as in Example 14A), 1.54 ml. of hydrazine hydrate and 2.23 g. of potassium hydroxide in 28 ml. of ethylene glycol is heated to reflux. Distillate is collected until the pot temperature rises to 200° C. and refluxing is continued for about 18 hours. The mixture is poured into water and a precipitated material is extracted with ether. The combined extracts are washed with water and brine and then evaporated to dryness. The residue is recrystallized from petroleum ether to give 2.39 g. (69.5% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one, 2,2-dimethyltrimethylene ketal(q) having a melting point of 109° to 111° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[Na+].[OH-].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Pd].O>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=C[O-]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Yield: 66.2 %

Procedure:
Bromobenzene (15.7 parts), cetyltrimethylammonium bromide (4.0 parts), 3% palladium on charcoal (50% paste; 2.0 parts), sodium formate (6.8 parts) and sodium hydroxide liquor (32%; 27 parts) in water (60 parts) are stirred at the boil under reflux for 4 hours. Sodium formate (6.8 parts) is then added and the mixture held at the boil under reflux for a further 18 hours. The mixture is then steam distilled. The steam distillate is extracted with chloroform (3 × 50 parts) and then the extract dried over anhydrous magnesium sulphate. After filtering off the drying agent the solvent is removed under vacuum to give 5.1 parts (66.2%) of biphenyl.
Reaction SMILES: CC(C)([O-])C.[K+].[Li]CCCC.[CH3:12][O:13][O:14][C@H:15]1[C@H:20]([O:21][O:22][CH3:23])[C@@H:19]([CH2:24][O:25][O:26][CH3:27])[O:18][CH:17]=[CH:16]1.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:37]([Sn:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:33][CH2:34][CH2:35][CH3:36])[C:17]1[O:18][C@H:19]([CH2:24][O:25][O:26][CH3:27])[C@@H:20]([O:21][O:22][CH3:23])[C@H:15]([O:14][O:13][CH3:12])[CH:16]=1)[CH2:38][CH2:39][CH3:40]
Reactant: COOC[C@H]1OC=C[C@@H](OOC)[C@@H]1OOC
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@H](OOC)[C@H](OOC)[C@@H](COOC)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of potassium tert-butoxide (0.42 g, 3.75 mmol) in anhydrous THF (10 mL) was added nBuLi (4.13 mmol) at -78° C. After 15 minutes, tri-O-methoxy-D-glucal (Example 7, 0.194 g, 1.03 mmol) was added in THF (5 mL). After stirring for one hour, tributylstannyl chloride was added and the mixture was allowed to warm to room temperature at which time it was cooled to 0° C. and quenched with ammonium chloride (sat.) and extracted with ethyl acetate three times. The organic layer was washed with water and brine, dried (NaSO4), filtered and concentrated to yield the title compound (0.24 g, 49%) as a clear liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To an aqueous solution of 55 mmol (7.6 g) of p-hydroxybenzoic acid and 65 mmol (2.6 g) of sodium hydroxide in 200 ml of water was added 65 mmol (10.6 g) of carbobenzoxy chloride dropwise during cooling with ice. After 24 hours, the generated precipitate was washed with water, filtered, dried, and purified by column chromatography, to obtain 15.0 g of 4-carbobenzoxyoxybenzoic acid (m.p.: 181.9°-183.1° C.). (Yield: 99%)
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:34])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][O:23][C:24]=2[CH2:25][OH:26])=[N:14][CH:13]=1.C1(C)C=CC=CC=1>O1CCOCC1>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[C:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:34])=[CH:13][N:14]=3)=[C:24]([CH2:25][OH:26])[O:23][N:22]=2)=[CH:28][CH:29]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of isopropylamine (49.6 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M, 418 μL, 0.84 mmol) and isopropylamine (49.6 mg, 0.84 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=1:1 to 7:3) to afford the title compound (32 mg, 39%) as white solid. MS: m/e=386.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1.ClC1C=CC(C2N(CC3CCOCC3)N=C3C=2CCNCC3)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: Clc1ccc(-c2c3c(nn2CC2CCOCC2)CCNCC3)cc1
Product: Clc1ccc(-c2nn(CC3CCOCC3)c3c2CCNCC3)cc1

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (0.3 mmol) in place of 2-chloromethyl-thiophene. The title compound was obtained as a 2:1 mixture (25 mg) with 3-(4-chloro-phenyl)-2-(tetrahydro-pyran-4-ylmethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. Data for the mixture: MS (ESI): exact mass calculated for C19H24ClN3O, 345.16; found, m/z 346.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.47-7.23 (m, 4H), 4.10-3.78 (m, 4H), 3.37-3.14 (m, 8H), 3.06-2.67 (m, 2H), 2.02-1.93 (m, 1H), 1.42-0.97 (m, 4H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:31](N)(N)(=[O:33])=[O:32]>COCCOCCOC>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[NH:26][S:31]1(=[O:33])=[O:32])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)[Si](OCCCNCc1ccccc1N)(c1ccccc1)c1ccccc1
Solvent: COCCOCCOC
Product: CC(C)(C)[Si](OCCCN1Cc2ccccc2NS1(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of 2-{[(3-{[tert-butyl(diphenyl)silyl]oxy}propyl)amino]methyl}aniline (0.45 g, 1.1 mmol) and sulfamide (0.12 g, 1.3 mmol) in diglyme (5 mL) was added dropwise to a flask containing refluxing diglyme (3 mL) over 10 minutes. The reaction mixture was stirred at reflux for 1 hour, then cooled to room temperature and evaporated to a brown oil. The crude reaction product was purified by flash chromatography (SiO2, 3-30% ethyl acetate/hexanes) to afford 3-(3-{[tert-butyl(diphenyl)silyl]oxy}propyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.50 g, 95%) as a colorless oil:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][N:4]=1.[CH3:13]COCC>>[F:12][C:2]([F:1])([F:11])[C:3]1[N:4]=[CH:5][C:6]([CH:9]([OH:10])[CH3:13])=[CH:7][N:8]=1
Reactant: CCOCC
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Product: CC(O)c1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a magnetically stirred solution of methyl Grignard (19.9 mL of a 3 M solution in ether (Et2O), 59.7 mmol) in Et2O (167 mL) was added a solution of 2-trifluoromethylpyrimidine-5-carbaldehyde (9.56 g, 54.3 mmol) in Et2O (50 mL) at 0° C., and the resulting pale yellow solution was warmed to room temperature (RT) and stirred for 2.5 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (NH4Cl) (50 mL) at 0° C., and the mixture was warmed to RT. The phases were separated and the organic phase was dried over Na2SO4, filtered, and concentrated to give a light yellow oil (9.32 g crude). The oil was purified by flash chromatography (330 g SiO2, 0→100% EtOAc/hexanes gradient) to give 1-(2-trifluoromethylpyrimidin-5-yl)ethanol (E) (8.87 g, 85%) as a light yellow solid: mp 43-45° C.; 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 2H), 5.15-5.07 (m, 1H), 2.26 (d, J=4.0 Hz, 1H), 1.62 (d, J=6.5 Hz, 3H); MS (EI) m/z 192 (M)+.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[S:16]([NH:19][C:20]1[C:21]([F:52])=[C:22]([C:26]2[N:27]=[C:28]([C:48]([CH3:51])([CH3:50])[CH3:49])[S:29][C:30]=2[C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C)[N:32]=2)[CH:23]=[CH:24][CH:25]=1)(=[O:18])=[O:17].CO>C(Cl)Cl>[NH2:40][CH2:39][CH2:38][NH:37][C:33]1[N:32]=[C:31]([C:30]2[S:29][C:28]([C:48]([CH3:51])([CH3:49])[CH3:50])=[N:27][C:26]=2[C:22]2[C:21]([F:52])=[C:20]([NH:19][S:16]([C:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=3[F:8])(=[O:17])=[O:18])[CH:25]=[CH:24][CH:23]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN)n2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.2 %

Procedure:
A 4 N solution of HCl in 1,4-dioxane (1.7 ml, 7.1 mmol) was added to a stirring solution of 1,1-dimethylethyl [2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]carbamate (0.31 g, 0.47 mmol) (composite batches prepared as described in the previous step) in DCM (10 ml) at rt. MeOH (1 ml) was added to aid in solubility. The reaction was allowed to stir at rt for 3 h. The volatiles were removed and the residue was dried in vacuo to afford the title compound of Step B (0.31 g, quantitative yield) as a hydrochloride salt that was used without further purification; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 7.93-8.18 (m, 4H), 7.20-7.69 (m, 7H), 3.37-3.53 (m, 2H), 2.96 (d, J=5.1 Hz, 2H), 1.41 (s, 9H). MS (ES+): 563 [M+H]+.