Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([Cl:40])[CH:39]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:35]=[C:34]([Cl:33])[CH:39]=[C:38]([Cl:40])[CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cc(Cl)cc(Cl)c3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (160 mg, 0.36 mmol, see step (b) Example 9) and 3,5-dichlorobenzeneboronic acid (140 mg, 0.72 mmol). Yield 100 mg (45%).
Reaction SMILES: [C:1]1([CH:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:8][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=2[Cl:39])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])([CH3:26])[CH:16]([CH:20]([CH3:25])[C:21]([O:23]C)=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.O.[OH-].[Na+]>[C:1]1([CH:7]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:8][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:30]=2[Cl:39])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:26])([CH3:27])[CH:16]([CH:20]([CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Yield: 92 %

Procedure:
A solution of methyl N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionate (195 mg, 0.3 mmole) in 10 mL of MeOH, 1 mL of H2O and 2 mL 2.5N NaOH was refluxed for 5 hours. The reaction was cooled, diluted with H2O and acidified with 3N HCl to pH 5.1. The mixture was extracted with EtOAc, the extracts were washed with H2O, dried and evaporated, and gave the titled compound, 172 mg (92% yield). MS (ESI) 625 (MH+).
Reaction SMILES: C(Cl)(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:15]([CH2:26][CH3:27])=[N:14][C:13]=1[C:28]#[N:29]>C(O)C>[NH2:29][C:28]1[C:13]2[N:14]=[C:15]([CH2:26][CH3:27])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: CCc1nc(C#N)c(-c2ccccc2N)n1CCCCNS(C)(=O)=O
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of acetyl chloride (0.15 mL, 2 mmol) in ethanol (2 mL) was added to a solution of N-{4-[5-(2-aminophenyl)-4-cyano-2-ethyl-1H-imidazo 1-yl]butyl}methanesulfonamide (0.19 g) in ethanol (4 mL). The mixture was heated at reflux for two hours, allowed to cool to room temperature, and concentrated under reduced pressure. The resulting off-white solid was dissolved in water (2.0 mL) with heating to 60° C. The resulting solution was adjusted to pH 12 with the addition of 10% w/w sodium hydroxide (about 0.2 mL). The mixture was cooled overnight at 5° C. The crystals were collected by filtration, washed with water, and dried under vacuum at 40° C. for two hours to provide N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as beige crystals, mp 202° C. to 204° C., having a 1H NMR spectrum consistent with an authentic sample.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[Cl:29])=[C:14]([Cl:30])[CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[Cl:29])=[C:14]([Cl:30])[CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)c(Cl)c2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
Powdered potassium hydroxide (0.045 g, 0.81 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-dichlorobiphenyl-4-yl)acetate (Intermediate 22-1; 0.12 g, 0.27 mmol) in tert-butanol (2.00 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 20 minutes. A thick precipitate formed so the reaction was quenched with HCl (1.620 mL, 1.62 mmol) in ethanol (20.0 mL) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was partitioned between water (5 mL) and EtOAc (15 mL). The aqueous layer showed a pH=4˜5. The organic layer was separated and the aqueous re-extracted with EtOAc (2×5 mL). The combined organics were washed with brine (15 mL), dried over MgSO4 and evaporated in vacuo to give product. This was washed with ether (5 mL) and dried under vacuum at room temperature to give an off white solid. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% ammonia) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-dichlorobiphenyl-4-yl)acetic acid (0.063 g, 51.7%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.C([Mg]Cl)(C)C.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[C:9]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[CH:26]=[O:27])([CH3:12])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(F)cc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)cc(C=O)c1
Reaction time: 0.75 h

Procedure:
Bromo-3-tert-butyl-5-fluorobenzene (323.2 g, 1.4 moles) was dissolved in THF (3.3 L) and cooled −10° C. iPrMgCl (2M solution in THF, 0.5 eq, 350 mL) was added over 20 min, followed by nBuLi (2.5M solution in hexanes, 1.0 eq, 560 mL) over two hours. DMF (4 eq, 450 mL) was added over one hour then stirred for 45 minutes and quenched with 3M HCl (1000 mL). The layers were separated and the aqueous fraction was diluted with water (1 L) and extracted with ethyl acetate (1 L). The organic fractions were combined and washed with water (2×2 L). The organic fraction was concentrated to provide an orange oil (252 g, quant), used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:47][C@@H:48](O)[CH2:49][CH:50]=[CH2:51].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:46])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[O:33][C@H:50]([CH2:49][CH:48]=[CH2:47])[CH3:51])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H](C)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O)c4)nn23)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.27 g, 0.43 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.132 mL, 1.28 mmol, 3 equiv), and PPh3 (0.23 g, 0.86 mmol, 2 equiv) in THF (2.1 mL) was added DIAD (0.166 mL, 0.86 mmol, 2 equiv). After stirring 18 h, diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a colorless glass (0.29 g, 97%). LCMS (M+1)=699.45.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: BrCC1CC1
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(CCOCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension under nitrogen of 656.5 mg (16.4 mmol) of NaH (at 60% in oil) in 15 ml of DMF is added over 10 minutes a solution of 3 g (14.9 mmol) of 2-(4-bromophenyl)ethanol in 5 ml of DMF. After stirring for 30 minutes at room temperature, the reaction medium is cooled to 10° C. and a solution of 2.4 g (17.9 mmol) of (bromomethyl)cyclopropane in 10 ml of DMF is added over 15 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:49]=[CH:48][C:27]([C:28]([N:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3/[C:34](=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])/[C:33]([F:47])([F:46])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:47][C:33]1([F:46])[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:49][CH:48]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2/[C:34]/1=[CH:41]/[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3cccc(C)c3)cc2)CCC1(F)F
Yield: 90.9 %

Procedure:
Using 277 mg of 2-(3-methylphenyl)benzoic acid, 0.127 ml of oxalyl chloride and 180 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 249 mg of methyl (Z)-[4,4-difluoro-1-[4-[2-(3methylphenyl)benzoylamino]benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=2)([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Reactant: Fc1cccc(I)c1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2Sc2cccc(F)c2)CC1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 1-fluoro-3-iodo-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:44][C:3]=1[CH2:4][N:5]([CH:41]1[CH2:43][CH2:42]1)[C:6](=[O:40])[CH:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]2[C:33]([Cl:34])=[CH:32][C:31]([CH2:35][CH2:36][CH2:37][OH:38])=[CH:30][C:29]=2[Cl:39])=[CH:20][CH:19]=1)[CH2:8][NH:9]C(=O)OC(C)(C)C.Cl>C(Cl)Cl>[NH2:9][CH2:8][CH:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]2[C:29]([Cl:39])=[CH:30][C:31]([CH2:35][CH2:36][CH2:37][OH:38])=[CH:32][C:33]=2[Cl:34])=[CH:20][CH:19]=1)[C:6]([N:5]([CH2:4][C:3]1[CH:44]=[C:45]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:2]=1[Cl:1])[CH:41]1[CH2:42][CH2:43]1)=[O:40]
Reactant: COCCCc1ccc(Cl)c(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(CCCO)cc3Cl)cc2)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1ccc(Cl)c(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(CCCO)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a CH2Cl2 solution (0.1 M) of tert-butyl [3-[[2-chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-2-(4-{2-[2,6-dichloro-4-(3-hydroxypropyl)phenoxy]ethoxy}benzyl}-3-oxopropyl]carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 35 eq.). The resulting solution was stirred at RT for 4 h. The reaction was quenched with 2.0 M NH3 in MeOH and concentrated in vacuo. The resulting residue was directly loaded onto a SiO2 column packed with 90:9:1 (v/v) CH2Cl2:MeOH:conc. NH4OH. Elution with the same solvent system furnished the title compound. MS (ESI+): 677.2.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH2:28]([O:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:38][C:37]1[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=1[O:35][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1OCc1ccccc1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
6.38 g of sodium triacetoxyborohydride (30.1 mmol) was added to a solution of 4.68 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (25.0 mmol), 5.0 g of 2-benzyloxyaniline (25.0 mmol) and 1.44 ml of acetic acid (25.0 mmol) in methylene chloride (250 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 8.50 g of the title compound (yield: 91%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10]([C:12]2[S:20][C:15]3=[N:16][CH:17]=[CH:18][N:19]=[C:14]3[CH:13]=2)=[O:11])[CH:8]=1.C[Al](C)C.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34](OC)=[O:35])=[CH:27]1>C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][CH:40]=[C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)[CH:32]=2)=[CH:8][C:7]=1[NH:9][C:10]([C:12]1[S:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1)=[O:11]
Reactant: COC(=O)c1cccc(-c2ccsc2)c1
Reactant: Cc1ccc(N)cc1NC(=O)c1cc2nccnc2s1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(-c3ccsc3)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a suspension of N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride 29 (73.5 mg, 0.229 mmol) in toluene (1.5 mL) was added trimethylaluminum (0.458 mL, 0.916 mmol) and was stirred for 15 min. methyl 3-(thiophen-3-yl)benzoate 82 (50 mg, 0.229 mmol) in toluene (1.5 mL) was added. The reaction mixture was stirred overnight at 60° C. Quenched with a saturated solution of NaHCO3 and extracted twice with EtOAc. Organic layer was washed with brine, dried, and evaporated. Purification by HPLC gave the title compound N-(2-methyl-5-(3-(thiophen-3-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 83 (6 mg, 5%). NMR (400 MHz, DMSO-d6) 2.27 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.64-7.72 (m, 3H), 7.87 (d, J=7.8 Hz, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 8.01 (dd, 2.7 Hz and 1.6 Hz, 1H), 8.27 (t, J=1.6 Hz, 1H), 8.55 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.37 (s, 1H), 10.53 (s, 1H). (m/z)=471 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:30][NH2:31].Cl>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([NH:31][CH3:30])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Reactant: CN
Agent: Cl
Product: CNC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Example 147c) and methylamine;hydrochloride as starting materials and isolated (5.9 mg, 16%); MS (ESI, m/z): 428.4 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[CH3:20][O:21][P:22]([O:25]C)[O:23][CH3:24]>>[Cl:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:2][P:22](=[O:25])([O:23][CH3:24])[O:21][CH3:20])[N:4]2[CH3:19])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: COP(OC)OC
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Product: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Reaction time: 1.25 h
Yield: 76.5 %

Procedure:
A mixture of 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.25 g, 0.72 mmol) and trimethylphosphite (4.0 mL, 34 mmol) was stirred at 120 degree for 1.25 hours. The resulting suspension was partitioned between water and dichloromethane. The aqueous layer was neutralized and extracted again with dichloromethane. The organic extracts were washed with water, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (0-5% methanol in DCM) to give the title compound (207 mg, 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl.C([O-])(O)=O.[Na+]>[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2cccc(Cl)c2Cl)CCN1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a suspension of 2-piperazinone (5.3 g, 52.9 mmol) in dry dichloromethane (DCM) (76 ml) was added triethylamine (16.23 ml, 116 mmol) and finally 2,3-dichlorobenzoyl chloride (12.20 g, 58.2 mmol) dropwise (exothermic). The mixture was stirred at room temperature. After 1 hour the mixture was diluted with DCM (150 mL) and sat. NaHCO3 (150 ml), the phases were separated and the aqueous layer extracted with DCM (2×100 ml). The combined organic fractions were washed with brine and dried over MgSO4. Evaporation gave 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (12 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.CCOCC>[CH2:15]([S:22][C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: Fc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(SCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
To a suspension of cesium carbonate (3.76 g, 11.5 mmol) in DMF (20 mL) at room temperature was added 5-chloro-2-fluoropyridine (1.00 mL, 9.96 mmol) and benzylmercaptan (1.15 mL, 9.80 mmol). The reaction mixture was stirred at room temperature for 16 h and heated to 60° C. for 6 h. The reaction mixture was diluted with Et2O. The organic phase was washed with water (2×), brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 10% EtOAc in heptane) to give the title compound (2.33 g, 9.88 mmol, 101% yield) as a colorless oil that was used without further purification in the next step. MS) m/z=236.1 [M+H]+. Calculated for C12H10ClNS 235.0.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[C:11]2=[O:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:31][CH:30]=3)[C:11]2=[O:29])=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc([N+](=O)[O-])cc3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc(N)cc3)c3ccccc32)cc1

Procedure:
Palladium-on-charcoal (5%, 650 mg) was added to a solution of 1-(4-tert-butylbenzyl)-3-(4-nitrobenzyl)-1,3-dihydrobenzimidazol-2-one (P) (1.13 g, 2.73 mmol) in abs. MeOH (60 mL). The reaction mixture was subjected to a hydrogen pressure of 3 bar for 20 min at RT. The catalyst was separated by filtration, and the filtrate was concentrated in vacuo. The residue was taken up in EtOAc (10 mL) and filtered through a frit with kieselguhr (layer thickness 1 cm). The frit was washed with ethyl acetate (4×20 mL). The desired product 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-1,3-dihydrobenzimidazol-2-one (Q) was obtained in a yield of 960 mg (91% of theory). The corresponding hydrochloride was obtained by reaction of 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-1,3-dihydrobenzimidazol-2-one (Q) with chlorotrimethylsilane (1 mL, 7.9 mmol) in DCM (50 mL). The reaction mixture was stirred over a period of 17 h without exclusion of moisture, and the resulting solid matter was separated with the aid of a frit and then dried. The hydrochloride was obtained as solid matter (750 mg, 68% of theory, mp: 198-219° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12](=O)[CH2:13]Br)=[N:10][CH:11]=1)=[O:5])C.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:9]3[N:10]=[CH:11][C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cnc(C(=O)CBr)nc1
Product: CCOc1ccc(-c2nc(-c3ncc(C(=O)O)cn3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-2-(α-bromoacetyl)pyrimidine and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-pyrimidyl)thiazole.