Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11]=2[N:21]=1.[NH2:22][C@@H:23]1[CH2:27][N:26]([C:28]2[CH:29]=[CH:30][C:31]3[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=3[N:37]=2)[C:25](=[O:39])[CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][C@@H:23]3[CH2:27][N:26]([C:28]4[CH:29]=[CH:30][C:31]5[O:32][CH2:33][C:34](=[O:38])[NH:35][C:36]=5[N:37]=4)[C:25](=[O:39])[CH2:24]3)[C:11]=2[N:21]=1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2n1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCCN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
Acetic acid (0.06 g, 1 mmol) was added dropwise to a mixture of 3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (synthesized with reference to WO2008/9700; 0.2 g, 0.85 mmol), 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 0.25 g, 1.0 mmol) and N,N-dimethylformamide (4 ml). Sodium triacetoxyborohydride (0.23 g, 1.1 mmol) was gradually added under cooling on ice to the obtained mixture, which was then stirred for 10 minutes. The mixture was further stirred at room temperature for 2 hours, cooled on ice, a saturated sodium hydrogen carbonate aqueous solution was added thereto, and the resultant was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 45 mg (11%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33].C(N(CC)CC)C>O1CCCC1.CO>[OH:33][NH:32][C:25](=[NH:26])[C:24]1[CH:27]=[CH:28][C:21]([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
517 mg 4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile were dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol. 1.68 g hydroxylamine hydrochloride were added followed by the addition of 3.35 ml triethylamine. The reaction mixture was stirred at 65° C. for eight hours. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 550 mg N-hydroxy-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine as an oil. C22H18F3N3O3S (461,47), MS (ESI): 462.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([O:25]CC)=[O:24].[Li+].[OH-].Cl>C(OCC)(=O)C.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
A mixture of ethyl (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate (0.23 g, 0.63 mmol) and LiOH (0.10 g, 4.20 mmol) in MeOH/H2O (1/1, 20.0 mL) was stirred at ambient temperature for 20 hours. The mixture was acidified with 0.1 M HCl until pH 2-3. The solid was filtered off and dried to give the title compound (0.15 g, 70%): MS (ES−) m/z 336.3 (M−1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[N:11][C:10]([Cl:13])=[CH:9][N:8]=2)[N:6]=1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][C@H:30]1[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]1[O:36][CH3:37])=[O:28].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[CH2:34][CH2:35][C@H:30]([NH:29][C:27]([C:21]4[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=4[Cl:19])=[O:28])[C@H:31]([O:36][CH3:37])[CH2:32]3)[S:3][C:4]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1cnc(Cl)cn1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate (Intermediate 47, 120 mg, 0.3960 mM) was added to a solution of 3,4-dichloro-N-[(3R,4S)-3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (WO2006087543, 127 mg, 0.4158 mM) and N,N-diisopropylethylamine (159.6 mg, 1.247 mM) in N-methyl 2-pyrrolidinone (1.0 mL) and the resulting reaction mixture was stirred at 50-55° C. for 1 h. The reaction mixture was cooled to room temperature and then poured into water (40 mL). The resulting solid was collected by filtration and dried to afford ethyl 4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate 140 mg (90%) of as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=2[CH3:23])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:31][CH:30]=[CH:29]2.O.[C:52]([OH:56])(=[O:55])[CH:53]=O>>[C:47]([O:46][C:44]([N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][CH:53]([C:17]3[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[O:24])=[C:15]([CH3:23])[CH:16]=3)[C:52]([OH:56])=[O:55])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: Cc1cc(B(O)O)ccc1CCCC(=O)Nc1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Solvent: O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCCC(=O)Nc1cccc(C#N)c1
Yield: 46 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 55D (200 mg, 0.623 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 55E (200 mg, 46%) as an oil. MS (ESI) m/z 694.4 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)C.[NH3:25]>CO.ClCCl>[CH2:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([NH2:25])=[O:3])=[CH:6][CH:7]=2)[N:16]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCc1ccnc(-c2ccc(C(=O)OCC)cc2)n1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1

Procedure:
4.4 g. of 4-(4-n-heptylpyrimid-2-yl)-benzoic acid ethyl ester dissolved in 50 ml. of a methanol-dichloromethane (1:1) mixture are treated with 30 ml. of liquid ammonia in a laboratory autoclave and then heated to 90° for 5 hours (pressure: 16 atmospheres). The reaction mixture is evaporated to dryness and the poorly soluble amide separated from the unreacted educt, whereby there is obtained 4-(4-n-heptylpyrimid-2yl)-benzoic acid amide.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:26][C:20]4[C:19]5[C:23](=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=5)[NH:22][CH:21]=4)[C:28]([C:30]4[N:34]([CH3:35])[CH:33]=[C:32]([C:36]#[N:37])[CH:31]=4)=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: Cn1cc(C#N)cc1C=O
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C#N)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-methyl-1H-indole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carbonitrile. Mass: 468.26 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][CH2:37][OH:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:33]3[CH2:34][CH2:35][N:30]([CH2:36][CH2:37][OH:38])[CH2:31][CH2:32]3)=[O:29])[NH:10][CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CCO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 63.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-ethanol (65.0 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (48.3 mg, 63.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.B#B.CO>O1CCCC1>[CH2:3]([C:4]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]2[C:11]([CH2:12][OH:14])=[CH:15][CH:16]=[CH:17][C:18]=2[N:19]=1)[CH2:2][CH2:7][CH3:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NCc1ccccc1Cl
Agent: B#B
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.2 %

Procedure:
A suspension of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole-7-carboxylic acid (Example 3) (9.06 g, 26.4 mmol) in dry tetrahydrofuran (950 mL) under an argon atmosphere was treated dropwise with a solution of diborane in tetrahydrofuran (105.2 mL of 1M diborane). The mixture was stirred at ambient temperature overnight. The reaction was cooled, treated with excess methanol continuously and the solvents were evaporated. The residue was dissolved in methylene chloride, and the solution was washed well with water, dried and concentrated. The crude product was chromatographed over 500 g of silica gel with a gradient of methanol in methylene chloride to give about 5 g of product. This was boiled in 10% hydrochloric acid (100 mL) and then chilled. The yellow crystals were filtered to provide 4.78 g of 2-n-butyl-1-(2-chlorophenyl)methyl-7-hydroxymethyl-1H-benzimidazole hydrochloride; mp 223°-233.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][C:30](Cl)=[O:31].[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][C:30]([NH:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1)=[O:31]
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: O=C(Cl)COc1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)COc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A cis/trans mixture of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (800 mg) was initially introduced into the reaction vessel with 540 μl triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (approx. 15 mg) in 20 ml methylene chloride, 790 mg (3-chlorophenoxy)acetyl chloride (1.05 molar equivalents) were added dropwise at −20° C. and the mixture was stirred overnight, while warming to room temperature. For working up, the mixture was rendered alkaline (pH>10) with one molar sodium hydroxide solution and extracted with diethyl ether (3×20 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated to dryness. The crude product obtained (1.53 g) was chromatographed on silica gel (3.0×17 cm) with 100 ml diethyl ether followed by 500 ml diethyl ether/methanol (v:v=2:1). 346 mg of the more polar diastereoisomer of 2-(3-chlorophenoxy)-N-(4-dimethylamino-4-phenylcyclohexyl)acetamide were obtained and, as a solution in 5 ml 2-butanone and 5 ml ethyl acetate, were converted into the corresponding hydrochloride by addition of 16 μl water and 110 μl chlorotrimethylsilane (322 mg of a white solid, m.p. 220° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[N:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C

Procedure:
A solution of the acid (146) (53 mg, 0.084 mmol), and carbonyldiimidazole (29.4 mg, 0.181 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (50.3 mg, 0.415 mmol) and DBU (34.1 mg, 0.224 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between AcOEt and diluted HCl, the organic layer was washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography (EtOAc/CH2Cl2, 2:8) provided the desired product which was subsequently dissolved in a minimum of ethanol and diluted with water. Filtration of the precipitate afforded the title compound (14.8 mg, 24%) as a white powder, m/z=734 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([CH:8]3[CH2:11][CH2:10][CH2:9]3)[CH2:13][CH2:14]2)=[CH:25][CH:24]=1)=[O:29]
Reactant: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Triethylamine (66.5 g, 0.658 moles) was added to a solution of 4-[(1-Cyclobutyl-4-piperidinyl)oxy]aniline (81 g, 0.329 moles, obtained in preparation 1) in dichloromethane (1 L), at 0° C. under nitrogen atmosphere. Then the resulting mass was treated with a solution of chloro acetyl chloride (44.6 g, 0.395 moles) in dichloromethane (1 L) drop wise at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum and the crude compound thus obtained was purified by flash chromatography (methanol:chloroform, 2:8) to obtain the title compound 76.1 g (Yield: 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][S:38][CH2:39][CH2:40][NH2:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:41][CH2:40][CH2:39][S:38][CH3:37])=[O:24]
Reactant: CSCCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCSC)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-(methylthio)-ethylamine.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:46][CH2:47][CH3:48])[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:46][CH2:47][CH3:48])[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[NH:3][C:4](=[O:7])[O:5][N:45]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(Oc2cccc(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogen carbonate (0.79 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(3-methoxyphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.27 g, 53%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[N:20]=2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1.CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([OH:31])=[O:30])[N:20]=2)=[CH:34][CH:35]=1)=[O:12]
Reactant: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Yield: 87.1 %

Procedure:
575 mg (1.24 mmol) ethyl 2-[3-[4-(2-naphthamido)benzyl]-1H-indazol-1-yl]acetate was dissolved in a mixed solution of 10 mL tetrahydrofuran and 3 mL methanol, in an ice bath 10 mL aqueous solution dissolving 333 mg (7.93 mmol) lithium hydroxide monohydrate was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, the pH value was adjusted to be acidic with diluted hydrochloric acid. A solid precipitated, it was filtered, dried to obtain a white solid 470 mg (1.08 mmol), at a yield of 87.1%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:7]1[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: OB(O)c1ccccc1F
Reactant: CON(C)C(=O)c1ccc2cccnc2c1OS(=O)(=O)C(F)(F)F
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1ccc2cccnc2c1-c1ccccc1F
Temperature: 100 °C
Yield: 78.6 %

Procedure:
To a mixture of 7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.15 g, 0.41 mmol) and (2-fluorophenyl)boronic acid (0.069 g, 0.49 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate (0.065 g, 0.62 mmol) in water (0.62 mL, 34 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated and purified on silica gel (0-100% EtOAc in Hexane) to give the desired product (100 mg, 78%). LCMS calculated for C18H16FN2O2(M+H)+: m/z=311.1; found: 311.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Oc1cccnc1Cl
Temperature: 90 °C

Procedure:
A 50 mL round bottom flask was charged with 2-chloropyridin-3-ol (2.5 g, 19 mmol), 2-fluorobenzonitrile (2.6 g, 21 mmol) and potassium carbonate (6.7 g, 48 mmol) in DMF (10 mL) and heated at 90° C. for 1.5 days. Water was added water, and the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10-20% ethyl acetate in hexanes as eluent to afford the title compound as an off white solid (2.1 g, 47% yield).