Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=O)[CH:2]=[CH2:3].[CH:24]([NH2:27])([CH3:26])[CH3:25].CO.[BH4-].[Na+]>O.C(O)(=O)C>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][NH:27][CH:24]([CH3:26])[CH3:25])[CH:2]=[CH2:3]
Reactant: C=CCNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C=CCNc1cc(CNC(C)C)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3-allylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g; prepared as described in Example 91), isopropylamine (4.0 ml) and methanol (100 ml) is stirred at 22°-25° C. for 24 hours and is then refluxed for 2 hours. To the stirred solution, sodium borohydride (4.0 g) is added in small portions during about 45 minutes, keeping the temperature at 0°-5° C. by external cooling. After the addition is completed, the reaction mixture is stirred at 0°-5° C. for a further 2 hours, whereafter acetic acid (4 ml) followed by water (300 ml) are cautiously added to precipitate crude (3-allylamino-4-phenoxy-5-sulfamylbenzyl)isopropylamine. After filtration and recrystallization from aqueous ethanol it is obtained with a melting point of 98°-100° C. The material (IR, analysis) is identical with the material prepared as in Example 113.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:50])[C:25]([C:27]4([NH:31][C:32](=[O:49])[CH:33]([NH:41][C:42]([O:44][C:45](C)(C)[CH3:46])=[O:43])[CH2:34][C:35]5([F:40])[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:30][CH2:29][CH2:28]4)=[O:26])=[N:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O>Cl.O1CCOCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:50])[CH:25]([C:27]4([NH:31][C:32](=[O:49])[CH:33]([NH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:34][C:35]5([F:40])[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:28][CH2:29][CH2:30]4)[OH:26])=[N:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(=O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 57-e (0.079 mmol) was dissolved in 4M HCl in dioxane (3 mL) and then stirred for 4 hrs at room temperature. The solution was concentrated under vacuum and the crude portioned between aq. K2CO3 (0.5 M) and DCM. The aqueous phase was extracted with EtOAc, the combined organic layers were dried over anh. Na2SO4 and concentrated under vacuum. The resulting amine was dissolved in dry DCM (3 mL) and an excess of solid NaHCO3 was added, followed by addition of ethyl chloroformate (7.5 μL, 0.079 mmol). The reaction was stirred for 2 hrs, then filtered and concentrated. (MS m/z 662.05 (M+H).+ The crude compound was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][Se:9][N:10]=[C:6]2[C:5]([S:11](Cl)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:21]C)[CH2:18][CH2:19][NH2:20])C.C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[C:7]2=[N:8][Se:9][N:10]=[C:6]2[C:5]([S:11]([NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c2n[se]nc12
Reactant: CCN(CC)CCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1ccc(F)c2n[se]nc12
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
7-fluoro-2,1,3-benzoselenadiazole-4-sulfonyl chloride (75 mg) was dissolved in 3 ml of acetonitrile. After the addition of N,N-diethylethylenediamine (22 mg) and triethylamine (351), the mixture was stirred on ice for 30 min. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in CH2Cl2 and chromatographed on silica gel using CH2Cl2-CH3OH (93:7) to yield 7-fluoro-N-[2-(dimethylamino)ethyl]-2,1,3-benzoselenadiazole-4-sulfonamide (49 mg, 56%) as red powder. mp: 117-120° C. 1H-NMR δH8.09 (1H, d, J=7.5 Hz), 7.24 (1H, d, J=7.5 Hz), 2.93 (2H, t, J=6.7 Hz), 2.27 (2H, t, J=6.7 Hz), 1.98 (6H, s) in CD3OD; ESI-MSm/z 353 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH2:51][CH2:52][O:53][CH2:54]C(O)=O)[CH:48]1[CH2:50][CH2:49]1)(=[O:46])=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH:48]1[CH2:50][CH2:49]1)[CH2:51][CH2:52][O:53][CH2:54][C:14]([N:11]1[CH2:10][CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:13][CH2:12]1)=[O:15])(=[O:46])=[O:45]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN2CCCC2)(c2cccc(F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(CCCN2CCCC2)(c2cccc(F)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A solution of tert-butyl 4-(3-fluorophenyl)-4-(3-(pyrrolidin-1-yl)propyl)piperidine-1-carboxylate (0.2379 mmol, 1.0 eq.) in dichloromethane (3 ml) was Boc-deprotected using standard reaction conditions (see step (vi)/example 25; TFA (3-13 eq.)) and added dropwise to a solution containing 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [carboxylic acid 2] (1 eq.), EDCI (1.5 eq), HOBt (1.0 eq.) and DIPEA (6.0 eq.) in dichloromethane (5 ml) at 0° C. The mixture was then stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and extracted with aq. ammonium chloride, aq. sodium hydrogen carbonate and water respectively. The organic layer was dried over sodium sulfate, concentrated in vacuo and the crude product purified by column chromatography (silica). Yield: 30%
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:8]([C:6]5[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:23]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: CCn1cc(C(=O)O)c(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)c(C)n1
Yield: 54.4 %

Procedure:
In the same manner as in Example 55 and using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (69.1 mg, 0.448 mmol), tetrahydrofuran (5 mL), thionyl chloride (78.0 μL, 0.899 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (132 mg, 0.408 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (102 mg, 55%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([CH3:25])[CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([CH3:22])=[C:17](C=O)[CH2:16][CH2:15]3)=[CH:4][CH:3]=1.CNCCC([O-])=O.Cl.[NH:34]1[CH2:37][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([CH3:25])[CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([CH3:22])=[C:17]([CH2:35][NH:34][CH2:37][CH2:36][C:38]([O:40][CH3:41])=[O:39])[CH2:16][CH2:15]3)=[CH:6][CH:7]=1
Reactant: CC1=C(C=O)CCc2cc(OC[C@@H](C)Cc3ccc(Cl)cc3)ccc21
Reactant: COC(=O)C1CNC1
Agent: CNCCC(=O)[O-]
Agent: Cl
Product: COC(=O)CCNCC1=C(C)c2ccc(OC[C@@H](C)Cc3ccc(Cl)cc3)cc2CC1

Procedure:
The procedure of Example 6 was similarly performed while using 6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde as a substitute for the compound prepared in Example 5 and using methyl-β-alaninate as a substitute for methyl azetidine-3-carboxylate hydrochloride. Thus, the title compound having the following physical properties was obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([NH:14][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)/C=C\C(=O)NC1CCCCC1

Procedure:
To a solution of 98 g of maleic anhydride in 500 g of toluene, 99.2 g of cyclohexylamine was added dropwise at a temperature in the range of 50° to 70° C. while in a stirred state. After the dropwise addition, the resultant mixture was stirred for two hours. Consequently N-cyclohexyl maleinamic acid was obtained. Then, the reaction solution and 14 g of methanesulfonic acid, 8.7 g of methanesulfonic acid-N-cyclohexyl maleinamate, and 15 g of N-methyl pyrrolidone added thereto were left reacting at 115° C. for 3.5 hours in a refluxed state, with the formed water continuously expelled from the reaction system through azeotropic distillation with toluene.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2].[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].CN1C(=O)CCC1>O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:2])[CH3:3]
Reactant: NCC(N)=O
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(OS(=O)(=O)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(NCC(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 85 °C
Yield: 16.5 %

Procedure:
A mixture of trifluoro-methanesulphonic acid 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl ester (174 mg, 0.38 mmol), 2-amino-acetamide (281 mg, 3.8 mmol) and NMP (2 mL) was heated at 85° C. for 18 hours. The reaction mixture was treated with water and stirred, the precipitate formed collected by filtration. The aqueous filtrate was passed down an Isolute SCX-2 cartridge washing with methanol and eluting with 2M ammonia in methanol. Appropriate fractions were combined and concentrated in vacuo, the resultant residue subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 458 (24 mg, 17%). LCMS: RT=2.18 min, [M+H]+=383. 1H NMR 400 MHz (DMSO-d6) δ: 9.00 (1 H, s), 7.78 (1 H, s), 7.31 (1 H, br, s), 7.00 (1 H, br, s), 6.94 (1 H, br, t), 6.10 (1 H, s), 5.85 (1 H, m), 4.47 (4 H, m), 3.83 (2 H, d, J=5.85 Hz), 2.25 (3 H, s), 1.45 (6 H, d, J=6.61 Hz)
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[C:63]([CH3:75])=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:86]1[CH2:91][CH2:90][N:89]([C:92]([O:94][C:95]([CH3:98])([CH3:97])[CH3:96])=[O:93])[CH2:88][CH2:87]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:52]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[C:63]([CH3:75])=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:50]=[CH:49][C:48]=1[CH:86]1[CH2:91][CH2:90][N:89]([C:92]([O:94][C:95]([CH3:98])([CH3:97])[CH3:96])=[O:93])[CH2:88][CH2:87]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)cc12
Yield: 88.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (200 mg, 0.271 mmol) was hydrolyzed by lithium hydroxide (57 mg, 1.356 mmol) in THF/methanol/water (5/4/1 ml) to yield 140 mg (88.6% yield) of the titled compound. MS: m/z=584.5 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH2:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([NH:30][CH3:29])=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: Cl
Product: CNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (75 mg) was coupled to methylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 38.8 mg of 171. MS (Q1) 395.1 (M)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[CH2:19]([OH:22])[C:20]#[CH:21]>C(N(CC)CC)C.[Cu]I>[CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([C:21]#[C:20][CH2:19][OH:22])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: C#CCO
Reactant: CCC(CC)C[C@@H](C)OC(=O)c1ccc(I)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC(CC)C[C@@H](C)OC(=O)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A schlenk tube was charged with 62.5 mg of dichlorobistriphenylphosphine palladium (II) complex and 45.5 mg of copper (I) iodide, and an atmosphere in the system was replaced with nitrogen. 31.9 Grams of p-iodobenzoic acid-(R)-3-ethyl-1-methylpentyl ester and 7.50 g of 2-propyn-1-ol were dissolved in 100 mL of dry triethylamine, and the mixture was charged into the above schlenk tube and stirred at room temperature for 1 day.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:29])=[C:14]([C:16]([CH3:28])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[OH:17])[CH:15]=1>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:29][CH:2]([C:3]([OH:5])=[O:4])[O:17][C:16]([CH3:28])([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:14]=2[CH:15]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(O)(c1cccc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2cccc(C(F)(F)F)c2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
A solution of 19.33 g of dichloroacetic acid in 200 ml of anhydrous dioxane was added dropwise at room temperature with stirring to a mixture of 16.8 g of sodium hydride in a 50% oil suspension, 150 ml of anhydrous dioxane and 1.6 g of dibenzo-18-courone-6 and then a solution of 31.7 g of 5-chloro-2-hydroxy-α-methyl-α-(3-trifluoromethylphenyl)-benzene-methanol in 200 ml of dioxane was added thereto dropwise. The mixture was progressively heated to 80° C. and was held there for 5 hours and then was cooled. The mixture was poured into ice and the aqueous phase was extracted with 400 ml of ether and was then acidified with 30 ml of concentrated hydrochloric acid. The aqueous phase was then extracted 3 times with 350 ml of methylene chloride and the organic extracts were washed twice with 200 ml of water and was extracted 4 times with 250 ml of an aqueous saturated sodium bicarbonate solution. The aqueous phase was washed with 200 ml of ether and was acidified with 80 ml of concentrated hydrochloric acid. The aqueous phase was then extracted 4 times with 200 ml of water and the ether extracts were washed 5 times with 100 ml of water, dried over magnesium sulfate, treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 28.4 g of raw 6-chloro-4-methyl-4-(3-trifluoromethylphenyl)-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@:11]1([NH:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[C:16](=[O:17])[C@@:15]2([CH2:18][OH:19])[C@H:13]([O:14]2)[C@@H:12]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:44][C:45]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])[CH3:46].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[C:16](=[O:17])[C@@:15]2([CH2:18][O:19][Si:48]([C:45]([CH3:47])([CH3:46])[CH3:44])([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
A flame-dried 25-mL round-bottomed flask was charged with alcohol 11 (1.0 g, 1.9 mmol, 1.0 equiv) and CH2Cl2 (9.5 mL). NEt3 (0.8 mL, 5.7 mmol, 3.0 equiv) and DMAP (0.023 g, 0.19 mmol, 0.1 equiv) were added and the solution was cooled 0° C. TBDPSCl (1.47 mL, 5.7 mmol, 3.0 equiv) was added dropwise and the reaction was warmed to rt and stirred for 8 h. Saturated NH4Cl(aq.) (10 mL) was added and the mixture was extracted with Et2O (3×15 mL). The combined organic extracts were washed with brine (10 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (70:30 hexanes:EtOAc) to give the title compound as a pale yellow oil (1.1 g, 76%). Analytical data: [α]D19 −4.4 (c=0.70, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.67 (d, J=7.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 2H), 7.44-7.30 (m, 11H), 5.68 (d, J=10.2 Hz, 1H), 5.23 (d, J=12.0 Hz, 1H), 4.97 (d, J=12.6 Hz, 1H), 4.74 (dd, J=3.0, 7.2 Hz, 1H), 4.70 (br s, 1H), 4.26 (d, J=12, 6 Hz, 1H), 4.11 (d, J=3.0 Hz, 1H), 4.03 (q, J=6.0 Hz, 1H), 3.92 (d, J=12.0 Hz, 1H), 2.68 (s, 6H), 1.19 (d, J=6.0 Hz, 3H), 1.01 (s, 9H), 0.92 (s, 9H), 0.13 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 203.9, 156.8, 156.0, 136.7, 135.5, 135.4, 132.6, 132.3, 129.8, 129.7, 128.3, 128.1, 127.9, 127.8, 127.7, 74.1, 69.4, 66.4, 66.2, 60.8, 57.5, 52.2, 36.1, 26.6, 25.6, 19.1, 18.3, 17.8, −3.8, −4.8; LRMS (ESI+) Calcd. for C41H57N3O7Si2+H, 760.38. Found, 760.31. IR (thin film, cm−1) 3419, 2931, 2857, 2359, 1716, 1651, 1507, 1226, 1113, 828, 733; TLC (70:30 hexanes/EtOAc): Rf=0.30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](Br)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Br-].[CH:33]1([Zn+])[CH2:37][CH2:36][CH2:35][CH2:34]1.O1CCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: [Zn+]C1CCCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C2CCCC2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a mixture of {(R)-4-[(3-bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (example 2-5) (prepared by the method analogous to the one described for example 2-1) (290 mg, 0.556 mmol) and a solution of cyclopentylzinc bromide in tetrahydrofuran (0.5 M, 10.0 mL, 5.0 mmol), bis(dibenzylideneacetone)palladium(0) (16.7 mg, 0.028 mmol) and tris(tert-butyl)phosphine (178 μL, 0.056 mmol) were added under an argon atmosphere. After being stirred at 50° C. for 1 hour, the mixture was concentrated in vacuo. Saturated ammonium chloride was added and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with saturated ammonium chloride, dried over sodium sulfate and concentrated in vacuo to afford {(R)-4-[(3-cyclopentyl-5-trifluoromethyl-benzene-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (220 mg, 77%) as a viscous oil which was used for the next step without any purification. MS cald. for C24H30F3N3O4S 513, obsd. (ESI+) [(M+H)+] 514.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(Cl)ccc12
Product: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1O

Procedure:
7-Chloro-4-hydroxyquinoline (35 g, 0.195 mol; available from Aldrich, Milwaukee, Wis.) and nitric acid (350 mL of 70%) were combined and heated at reflux for 75 minutes. The reaction mixture was poured over ice while still hot. The resulting bright yellow precipitate was isolated by filtration and then washed 3 times with boiling ethyl acetate to provide 17.3 g of 7-chloro-3-nitro-4-hydroxyquinoline as a pale yellow solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[O:13][CH:14]([CH3:18])[C:15](=[O:17])[NH:16][C:11]=2[CH:10]=[C:9]([CH:19]=[O:20])[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:12]2[O:13][CH:14]([CH3:18])[C:15](=[O:17])[NH:16][C:11]=2[CH:10]=[C:9]([CH:19]=[O:20])[CH:8]=1
Reactant: COc1cc(C=O)cc2c1OC(C)C(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1Oc2c(O)cc(C=O)cc2NC1=O
Temperature: 23 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a 200 mL round-bottomed flask cooled in an ice/brine bath was added BBr3 (3.4 g, 13.56 mmol) in DCM (30 mL) under N2. A solution of 17 in DCM (10 mL) was added drop-wise to the cooled BBr3 solution. The reaction was stirred under N2 for 1 hr, then allowed to warm to 23° C. After 2 hr, the reaction was poured over ice and the resulting solid was isolated by vacuum filtration, washed with water, and dried in vacuo to give a tan solid (0.722 g, 77% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.50 (m, 3H) 4.76 (q, J=6.74 Hz, 1H) 6.93 (d, J=2.02 Hz, 1H) 7.04 (d, J=2.02 Hz, 1H) 9.72-9.77 (m, 1H) 9.95-10.01 (m, 1H) 10.85 (s, 1H). ESI-MS: m/z 208.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COC(OC)c1ccccc1Br
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(C(O)c2ccccc2C(OC)OC)cc1OC
Yield: 89 %

Procedure:
2-bromobenzaldehyde dimethylacetal and 3,4-dimethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3,4-dimethoxy-α-hydroxybenzyl)benzaldehyde dimethylacetal is obtained as pale yellow syrup.