Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[CH:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (372 mg, 75%).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].[OH-].[K+]>C1COCC1>[C:19]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: C=CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-1,4-benzothiazepine (11 g) and triethylamine (13.5 g) were dissolved in THF (300 ml) and acryloyl chloride (9.5 g) was added dropwise thereto under ice cooling and agitated at room temperature for 30 minutes. A 10% potassium hydroxide aqueous solution was added thereto, agitated at room temperature and thereafter extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (60 parts) +ethyl acetate (40 parts) to give 4-acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (12.59).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>C1COCC1>[OH:2][CH:1]([C:22]1[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: CSc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 4-methylsulfanylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(4-methylsulfanyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH2:1]([N:19]([CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:20]([CH2:22][CH2:23][CH:24]([CH:26]1[C:42]2([CH3:43])[CH:29]([CH:30]3[CH:39]([CH2:40][CH2:41]2)[C:38]2([CH3:44])[CH:33]([CH2:34][CH:35]([O:45][C:46](=[O:86])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([N:55]4[CH2:59][CH:58]([OH:60])[CH2:57][CH:56]4[CH:61]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)[O:62][CH:63]([C:72]4[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=4)[C:64]4[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=4)=[O:54])[CH2:36][CH2:37]2)[CH2:32][CH2:31]3)[CH2:28][CH2:27]1)[CH3:25])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:105]1(=[O:111])[O:110][C:108](=[O:109])[CH2:107][CH2:106]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:71][O:70][C:67]1[CH:68]=[CH:69][C:64]([CH:63]([C:72]2[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=2)[O:62][CH:61]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[CH:56]2[N:55]([C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][NH:47][C:46]([O:45][CH:35]3[CH2:34][CH:33]4[C:38]([CH3:44])([CH:39]5[CH:30]([CH2:31][CH2:32]4)[CH:29]4[C:42]([CH3:43])([CH:26]([CH:24]([CH3:25])[CH2:23][CH2:22][C:20](=[O:21])[N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[CH2:27][CH2:28]4)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)=[O:86])[CH2:59][CH:58]([O:60][C:105](=[O:111])[CH2:106][CH2:107][C:108]([OH:110])=[O:109])[CH2:57]2)=[CH:65][CH:66]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)NCCCCCC(=O)N5CC(OC(=O)CCC(=O)O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
Referring to scheme 21, Compound 84 (1.44 g, 1 mmol) was mixed with succinic anhydride (0.15 g, 1.5 mmol) and DMAP (0.0122 g, 0.1 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.101 g, 0.14 mL, 1 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 25 mL) and water (2×25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 86 as white solid (1.1 g, 71% yield; Rf=0.5 in 10% MeOH/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][S:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[CH:19][CH:18]=3)[N:14]=2)=[C:4]([F:32])[CH:3]=1.ClC1C=C(C(OO)=[O:41])C=CC=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][S:22]([CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[O:41])=[CH:19][CH:18]=3)[N:14]=2)=[C:4]([F:32])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(CSCCn3ccnn3)cc2)co1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 320 mg (0.68 mmol) 1-[2-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 9 ml dichloromethane at −30° C. were added dropwise during 20 min 197 mg (0.88 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 9 ml ethyl acetate. After 1 hour stirring at 30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 20:1 furnished as the second fraction 171 mg (51%) title compound as white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][C:10]([NH:26]C(=O)OCC2C=CC=CC=2)([CH3:25])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[CH2:11][C:10]([CH3:25])([NH2:26])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)OCc2ccccc2)Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC1(N)Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1=O
Yield: 94.5 %

Procedure:
To a solution of 148F (340 mg, 0.69 mmol) in MeOH (8 mL) was added 5% palladium on carbon (200 mg). The resulting suspension was hydrogenated under hydrogen balloon for 1 h., then filtered. The filtrate was concentrated to give title compound (235 mg, 94% yield) as an off-white foam.
Reaction SMILES: Cl.[N:2]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3]1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O)(=O)/C=C\C(O)=O>C(O)C>[CH:6]1[N:2]2[C@H:7]3[C@H:8]([NH:13][C:15]4([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)[C:3]2=[CH:4][CH:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12]3
Reactant: N[C@@H]1CCCC[C@H]1n1cccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H]1CCCC[C@H]1n1cccc12
Temperature: 80 °C

Procedure:
trans-2-(1H-Pyrrol-1-yl)cyclohexanamine hydrogen chloride (989 mg, 4.93 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (982 mg, 4.93 mmol), and maleic acid (56.2 mg, 0.493 mmol) were combined in ethanol (12 mL). The reaction mixture was heated at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in dichloromethane and was then purified on 80 g of silica gel utilizing a gradient of 0-10% methanol in dichloromethane to give trans-tert-butyl 5a′,6′,7′,8′,9′,9a′-hexahydro-5′H-spiro[piperidine-4,4′-pyrrolo[1,2-a]quinoxaline]-1-carboxylate. ESI-MS m/z calc. 345.2, found 346.2 (M+1)+; Retention time: 1.63 minutes (4 min run).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:25]1[C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][C:23]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: O=Cc1ccc(Cl)cc1-n1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(C)n1c(-c2ccc(Cl)cc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
The 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (185 mg, 0.72 mmol) and 4-chloro-2-1,2,4-triazol-1-yl-benzaldehyde (150 mg, 0.72 mmol) are combined in methanol (5 mL) and warmed to 65° C. After 18 hours, catalytic TsOH is added and heating is continued at 65° C. for 48 hours. The reaction mixture is cooled to room temperature and concentrated. The residue is purified via flash chromatography (12 g silica gel, 0-10% MeOH/CH2Cl2). Product-containing fractions are combined and concentrated. The residue is diluted with acetonitrile and the resulting solid product is collected via filtration (55 mg, 17%). LCMS (ESMS): m/z 445.20 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH3:25])[NH:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(F)c21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:4])=[O:3].C[C:30]([CH3:33])([O-:32])[CH3:31].[K+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][C:8]([N+:25]([O-:27])=[O:26])=[C:7]([CH:12]=1)[C:6]([N:5]([C:6](=[O:28])[C:7]1[CH:33]=[C:30]([O:32][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[Cl:24])[CH:31]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])[S:2]([CH3:1])(=[O:4])=[O:3])=[O:28]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To N-methylsulfonyl-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro-benzamide (20.0 grams, 45.6 millimoles) dissolved in 100 ml tetrahydrofuran was added potassium tertiary butoxide in tetrahydrofuran with cooling. A solution of the acid chloride product as described in Example 1 in tetrahydrofuran was then added and the mixture stirred at ambient temperature for forty eight hours under nitrogen with precautions taken to exclude moisture throughout this procedure. The mixture was then diluted with toluene, washed three times with water and saturated sodium chloride solution. The organic phase was concentrated by vacuum to dryness. The residue was shaken with toluene then reconcentrated three times. The final residue was covered with toluene, shaken, the insolubles filtered off, and washed several more times with toluene and hexane. The material was triturated for 30 minutes by stirring with 50 ml hexane. The insolubles were filtered off and dried. The material was purified further by trituration with 5% potassium carbonate followed by drying and recrystallization from toluene/hexane mixtures. The desired product had a melting point of 165.5°-167.5° C.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH:12]=1)[C:10]#N)([F:4])[CH3:3].[OH2:18].Cl>C(Cl)Cl>[F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH:12]=1)[CH:10]=[O:18])([F:4])[CH3:3]
Reactant: O
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C#N)c1
Agent: Cl
Solvent: ClCCl
Product: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a stirred solution of Compound 24 (1.31 g, 5.22 mmol) in dry CH2Cl2(20 ml) was added a solution of diisobutylaluminum hydride(DIBAL) (6.20 ml, 6.26 mmol, 1.01M in toluene solution) with ice-cooling. The reaction mixture was stirred at 0° C. for 3 h. To the mixture was added H2O(6 ml), followed by 6M HCl aq. (20 ml) and stirred at room temperature for 1.5 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 aq. and brine, dried(MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (50:1-30:1) to give Compound 25 (1.17 g, 88%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>C(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:22]=[N:21][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc2ccc(CNc3ccc(C)cc3N)cc2s1
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(C)ccc43)cc2s1
Temperature: 100 °C
Yield: 85 %

Procedure:
A stirred mixture of crude 4-methyl-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (0.7 g, 2.3 mmol), formic acid (0.5 mL) and triethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.61 g, 85%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.26 (m, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 5.43 (s, 2H), 2.77 (s, 3H), 2.47 (s, 3H); LCMS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)Cl>[Br:16][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Cc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4-methylpyrimidine (10 g, 91.6 mmol), n-bromosuccinimide (17.9 g, 100.8 mmol) and CHCl3 are mixed together and stirred at room temperature for 1 hour. The solvent is removed in vacuo, water is added and the mixture is stirred at room temperature for 30 minutes. The resulting precipitate is collected by filtration and dried under vacuum oven to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1.[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[CH:28])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[C:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:9])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5-Chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone (2aa) (5.5 g, 14.5 mmol), prop-2-ynyl-carbamic acid tert-butyl ester (2.5 g, 16 mmol), PdCl2(PPh3)2 (0.6 g, 0.9 mmol) and Cu(I)I (0.2 g, 0.9 mmol) were suspended in anhydrous CH2Cl2 (50 mL) and the mixture was sparged with nitrogen for 30 min. Diethylamine (8 mL) was added and the solution was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the resulting residue purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to afford 3aa (3.6 g, 61%) as a white solid, MS m/z=406 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 108 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[C:9]([NH2:12])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:21][CH:22]([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[F:32][CH:22]([F:21])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:12][C:9]1[C:10]2[CH2:11][C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4][C:5]=2[CH:6]=[CH:7][CH:8]=1)=[O:26]
Reactant: CC1(C)CCc2cccc(N)c2C1
Reactant: O=C(Cl)c1cccnc1C(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CCc2cccc(NC(=O)c3cccnc3C(F)F)c2C1
Reaction time: 2 h

Procedure:
In a round bottom flask, 7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-1-amine (150 mg, 0.86 mmol, 1.0 eq.) was dissolved in 5 ml of THF. Triethylamine (0.104 mg, 1.02 mmol, 1.2 eq) was added followed by a solution of 2-(difluoromethyl)nicotinoyl chloride (180 mg, 0.94 mmol, 1.1 eq) in 1 ml of THF. Stirring was allowed for 2 h at r.t. The reaction was quenched with water, the organic layer extracted with AcOEt, washed with brine and dried over chemelut cartridge. The solvent was removed under vacuum and purification of the crude material by
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][C:17]([OH:19])=[O:18])[N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:18][C:17](=[O:19])[CH2:16][N:15]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)=[N:12][N:13]=[N:14]1
Reactant: CCCCc1ccc(-c2nnnn2CC(=O)O)cc1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: CCCCc1ccc(-c2nnnn2CC(=O)OCCO)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 47.4 %

Procedure:
To a solution of 1 g (3.84 mM) of [5-(4-butylphenyl) tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=9/1) for separation and purification, to give 550 mg (yield 47.4%) of [5-(4-butylphenyl) tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:28]([Si:30]([C:35]#[CH:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH3:29].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu]I>[N:23]1([CH2:22][CH2:21][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:29]#[C:28][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:3]=3)[N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCN3CCCC3)c3cc(Br)ccc32)cc1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc2c(c1)c(CCN1CCCC1)cn2S(=O)(=O)c1ccc(C)cc1)(CC)CC
Yield: 39 %

Procedure:
To a solution of 5-bromo-3-(2-pyrrolidinylethyl)-1-(p-toluenesulfonyl)-indole (Example 5, 415 mg, 1 mmol) in toluene (20 mL), were added triethylsilylacetylene (0.72 mL, 4 mmol, dichlorbis(triphenylphosphine) palladium (II) (210 mg, 0.3 mmol), copper (I) iodide (57 mg, 0.3 mmol) and triethylamine (1 mL). The resulting mixture was stirred under argon at reflux overnight and then evaporated to dryness. Chromatography on silica gel (ethyl acetate followed by methanol) gave the title compound as a yellow oil (197 mg, 39%).