Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1>O1CCCC1>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: CCCC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and butyryl chloride (0.380 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. The residue was washed with boiling methanol and dried in vacuo to give 0.773 g of brown powder; mp 276-277 ° C. (dec).
Reaction SMILES: C(OCC)(=O)C.[OH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH:13]=[CH2:14].[CH2:19]([N:37]=[C:38]=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(N(CC)CC)C>[CH2:19]([NH:37][C:38]([O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: C=CC(=O)Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cccc(OC(=O)NCCCCCCCCCCCCCCCCCC)c1
Temperature: 20 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 16.3 parts of 3'-hydroxyacrylanilide, 29.5 parts of octadecyl isocyanate and one part of triethylamine. The reaction mixture is heated at reflux for about 1 hour, cooled to 20°C and filtered. The solids are washed with ethyl acetate and air dried to give 40.5 parts of 3'-(octadecylcarbamoyloxy)acrylanilide, m.p. 124°-126°C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:56][CH:57]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.017 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 68% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:26]1([C:32]2[O:33][C:34]([C:40](F)(F)F)=[C:35]([C:37](O)=[O:38])[N:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([C:35]4[N:36]=[C:32]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:33][C:34]=4[CH3:40])=[O:38])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C)cn3)cc2C1=O
Yield: 43 %

Procedure:
The compound of example 654 was prepared analogous to the compound of example 640 by reaction of compound of example 392 with 2-phenyl-5-(trifluoromethyl)oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([C:3]([CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C(OCC)=O)#[N:2].O.[Br-].[Li+].Cl>CN(C)C=O>[CH3:19][Si:16]([CH3:17])([CH3:18])[CH2:15][CH:3]([C:1]#[N:2])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(C#N)(C[Si](C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C#N)C[Si](C)(C)C
Temperature: 150 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
A solution of diethyl 2-cyano-2-(trimethylsilylmethyl)succinate (592 mg, 2.08 mmol) in dimethylformamide (DMF, 5 ml) was added with water (45 μl, 2.50 mmol) and lithium bromide (217 mg, 2.49 mmol), and the mixture was stirred at 150° C. for 15 hours. The reaction mixture was cooled on ice, and added with aqueous hydrochloric acid (1 N), and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (14:1)] to obtain ethyl 4-trimethylsilyl-3-cyanobutanoate (404 mg, 91%) mentioned in the title as colorless oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH2:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([CH:21]3[CH2:20][CH2:19][N:18]([CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: CCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN1CCC(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (23 mmol), 4-(1-propyl-piperidin-4-yl)-benzoic acid hydrochloride (23 mmol), HOBT (23 mmol), WSCD (23 mmol) and triethylamine (23 mmol) are dissolved in DMF (50 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale powder with mp. 198-200° C., Rf=0.34 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[H-].[Na+].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:1][CH:2]([CH2:8][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1nc(-c2ccccc2)nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A solution of diethyl methylmalonate (23 g) in anhydrous tetrahydrofuran (100 cc) is added under nitrogen to sodium hydride (4 g, 80% strength in oil) and anhydrous tetrahydrofuran (60 cc). After 1 hour's stirring, a solution of 4-bromomethyl-2-phenylquinazoline (9.9 g) in anhydrous tetrahydrofuran (100 cc) is added, and the mixture is stirred for a further 2 hours at room temperature (approximately 20° C.). Water (100 cc) is added and the mixture is extracted with ethyl acetate (3×100 cc). The organic phase is dried over magnesium sulphate and then evaporated to dryness under reduced pressure. The residue is taken up in concentrated hydrochloric acid (100 cc) and acetic acid (100 cc) and the mixture is brought to 110° C. for 24 hours. After the mixture has cooled, the precipitate is filtered off and washed with water and then ispropyl ether. After being dried, α-methyl-2-phenyl-4-quinazolinepropanoic acid (4 g), m.p. 180° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=S)=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.[CH:39]1([C:42]([NH:44][NH2:45])=O)[CH2:41][CH2:40]1.C(Cl)Cl>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[CH:39]1([C:42]2[N:28]3[CH2:29][CH2:30][CH2:31][C@@H:26]([C:13]4[N:9]5[CH:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]6[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=6[O:2][CH3:1])[C:8]5=[C:15]([C:16]5[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=5)[N:14]=4)[C:27]3=[N:45][N:44]=2)[CH2:41][CH2:40]1
Reactant: NNC(=O)C1CC1
Reactant: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=S)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc([C@@H]3CCCn4c(C5CC5)nnc43)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a solution of (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-thioxopiperidin-3-yl) imidazo[1,5-a]pyrazin-1-yl)benzoate (600 mg, 1.13 mmol) in THF (20 mL) was added cyclopropanecarbohydrazide (339 mg, 3.39 mmol) and Hg(OAc)2 (360 mg, 1.13 mmol). The mixture was stirred at RT for 20 minutes and then heated to 65° C. overnight. The reaction mixture was filtered and the filtrate was evaporated, the residue was purified by column chromatography on silica gel eluted with EA:DCM:THF=1:1:1 to give (S)-methyl 4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (300 mg, yield 46%).
Reaction SMILES: CS([C:4]1[N:13]2[C:7]([C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)=O.[CH3:19][O-:20].[Na+]>>[CH3:19][O:20][C:4]1[N:13]2[C:7]([C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1
Reactant: CS(=O)c1nnc2c(=O)c3ccccc3ccn12
Reactant: C[O-]
Agent: [Na+]
Product: COc1nnc2c(=O)c3ccccc3ccn12

Procedure:
The reaction of 3-methylsulfinyl-11H-s-triazolo [3,4-b][3]benzazepin-11-one with sodium methoxide yielded 3-methoxy-11H-s-triazolo[3,4-b][3]benzazepin-11-one. Colorless platelets (as recrystallized from methanol), melting point: 149°-150° C.
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=3)=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3cc(O)ccc3o2)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (19.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2′,5′-dihydroxyacetophenone (6.4 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 4-methoxybenzoyl chloride (6.5 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 4′-methoxy-6-hydroxyflavone. 1H NMR (250 MHz, d6-DMSO): δ=3.73 (s, 3H), 6.6–8.5 (m, 8 H), 12.5 (s, 10 H); NMR (250 MHz, d6-DMSO): δ=56 (s), 94.9 (s), 114.0 (s), 117.6 (s), 118.9 (s), 122.2 (s), 126.6 (s), 127.2 (s), 150.5 (s), 152.0 (s), 161.2 (s), 168.8 (s), 187.0 (s) EI-MS (70 eV) m/e (rel. abund.)=268; UV (2-propanol): λ=254 nm, 323 nm.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][NH:12][C:11]3=O)=[N:5][N:4]=1.P(Cl)(Cl)([Cl:23])=O>C(N(CC)CC)C>[Cl:23][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]3[O:7][C:3]([C:2]([F:20])([F:19])[F:1])=[N:4][N:5]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=c1[nH]cnc2ccc(-c3nnc(C(F)(F)F)o3)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1

Procedure:
6-(5-Trifluoromethyl-1,3,4-oxadiazol-2-yl)quinazolin-4-one (0.79 g) was treated with phosphorus oxychloride (18 ml) and triethylamine (8 ml) at reflux under N2 for 2 hours. The mixture was concentrated in vacuo and the residue azeotroped with toluene. This was then taken up in ethyl acetate and washed with 5% sodium bicarbonate and saturated brine, dried over magnesium sulphate and concentrated in vacuo to give the title compound (0.76 g) as an orange solid; δH CDCl3 9.17(1H,s), 9.05 (1H,d), 8.69(1H,dd), 8.30(1H,d).
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br>>[CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[C:30]([F:29])([F:39])[F:40])[C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(Cc2ccccc2C(F)(F)F)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.147 g, 34%) from {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 2-trifluoromethyl benzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.72 (t, J=7.8 Hz, 3H), 1.08-1.29 (m, 4H), 1.51-1.67 (m, 2H), 2.71 (t, J=8.6 Hz, 2H), 5.29 (s, 2H), 5.47 (s, 2H), 6.37 (d, J=8.6 Hz, 1H), 7.08-7.21 (m, 2H), 7.23-7.32 (m, 2H), 7.35-7.45 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.63-7.75 (m, 2H), 7.83-7.92 (m, 3H); mass spectrum [(+) ESI], m/z 527 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cn[nH]c4)cc23)CC1

Procedure:
Following the general procedure of Example 66, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) were reacted to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23]([OH:25])=O)=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH:34]([CH3:37])[CH2:35][OH:36]>>[OH:36][CH2:35][CH:34]([NH:33][C:23]([C:21]1[S:22][C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])=[CH:32][C:19]=2[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[CH3:37]
Reactant: CC(N)CO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Product: CC(CO)NC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Yield: 29 %

Procedure:
According to Step 1, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with 2-amino-1-propanol (0.027 mL, 0.35 mmol) followed by chromatographic purification (silica gel, dichloromethane/methanol (0-10% methanol)) and recrystallization from ethyl acetate/hexane, the desired compound is obtained at 29% yield (51 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][NH:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[CH2:20]1)[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1)C1CCc2cc(F)ccc2C1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of benzyl((1R,2S)-2-{[((2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}cyclohexyl)carbamate (300 mg, 0.73 mmol) in acetonitrile (4 mL) was treated with formaldehyde (37% aqueous, 300 μL), sodium cyanoborohydride (138 mg, 2.19 mmol) and a few drops of acetic acid. After stirring at room temperature, the mixture was treated with aqueous sodium hydroxide (1.0 N) and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide a gum (280 mg, 90%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10])(=O)[CH3:2].[CH:11]([NH:13][NH2:14])=[O:12]>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:14][NH:13][CH:11]=[O:12])[CH3:2]
Reactant: NNC=O
Reactant: CC(=O)c1ccncc1Cl
Solvent: CCO
Product: CC(=NNC=O)c1ccncc1Cl

Procedure:
A mixture of 6.30 gm (0.0405 mole) of 4-acetyl-3-chloropyridine, 2.46 gm (0.041 mole) of formic acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer to give a solid which was collected in two crops. The product was purified by chromotography [keiselgel 60 (230-400 mesh)] and eluting with 5% methanol/methylene chloride to give 2.56 gm (32%) of white flakes which have a melting point of 175.2° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[N:33]1([C:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-4-hydroxycyclohexanecarboxylic acid (720 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.33 g, 6 mmol) and 1-hydroxy-7-azabenzotriazole (816 mg, 6 mmol) in dichloromethane (6 ml) was treated with morpholine 1.3 ml, 15 mmol). After stirring at room temperature for 18 hours, the crude reaction was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo, and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D55); MS (ES+) m/e 214 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]([CH:16]=1)[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.32 g, 1 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organic layers were separated and dried over sodium sulfate and concentrated in vacuo. The product used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([Cl:20])[N:11]=1>>[C:1]([O:5][C:6](=[O:8])[CH2:7][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([Cl:20])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After stirring at RT for 10 minutes, the clear dark red solution is cooled to −10° C. Acetic acid tert-butyl ester (15.7 ml, 13.5 g, 116.1 mmol) is added during 5 min. After 10 minutes at −10° C., 1,3-Dichloro-isoquinoline (10.0 g, 50.49 mmol) is added in one portion. The dark red solution is allowed to warm to RT. After 30 minutes at RT, TLC analysis indicates complete conversion of the starting material. The reaction mixture is filtered through a 2-cm pad of silica, which is rinsed with EtOAc/MeOH 98:2. After concentration, the residue is purified by FCC (toluene/CH2Cl2 2:1 to toluene/EtOAc 100:0 to 99:1 to 98:2 to 97:3 to 96:4 to 94:6 to 90:10) to afford (3-Chloro-isoquinolin-1-yl)-acetic acid tert.-butyl ester. This compound is dissolved in a saturated ethanolic solution of HCl (200 ml) and refluxed for 15 minutes. Concentration affords the title compound in quantitative yield. 1H NMR (DMSO, 400 MHz) δ 1.17 (t, J=8.8, 3H), 4.11 (q, J=8.8, 2H), 4.28 (s, 2H), 7.51-7.57 (m, 1H), 7.61 (s, 1H), 7.61-7.66 (m, 1H), 7.72 (d, J=8.8, 1H), 7.98 (d, J=8.8, 1H); ES-MS: 250 [M+H]+.