Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CN[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:21]=[C:22]([S:26]([C:29]3[CH:30]=[C:31]4[C:36](=[C:37]([CH3:39])[CH:38]=3)[N:35]=[CH:34][C:33]([C:40]([NH2:42])=[O:41])=[C:32]4[NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[CH:45]=3)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.[NH2:64][CH2:65][C@@H:66]([C:68]1[CH:73]=[CH:72][C:71]([OH:74])=[C:70]([CH2:75][O:76][Si:77]([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:79])[CH3:78])[CH:69]=1)[OH:67]>>[Si:77]([O:76][CH2:75][C:70]1[CH:69]=[C:68]([C@@H:66]([OH:67])[CH2:65][NH:64][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:21]=[C:22]([S:26]([C:29]4[CH:30]=[C:31]5[C:36](=[C:37]([CH3:39])[CH:38]=4)[N:35]=[CH:34][C:33]([C:40]([NH2:42])=[O:41])=[C:32]5[NH:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[CH:45]=4)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=3)=[O:19])[CH2:14][CH2:13]2)[CH:73]=[CH:72][C:71]=1[OH:74])([C:80]([CH3:83])([CH3:82])[CH3:81])([CH3:78])[CH3:79]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN)ccc1O
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(NC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)CC5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(NC[C@H](O)c6ccc(O)c(CO[Si](C)(C)C(C)(C)C)c6)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 150, using Intermediate 9 in place of Intermediate 2. ES/MS calcd. for C45H56N5O8SSi+ 854.4. Found m/z=854 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:28](O)=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1.[O:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=3)[C:28](=[O:29])[N:44]3[CH2:43][CH2:42][N:41]([CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH2:46][CH2:45]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1ccc(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: C1CN(C2CCOCC2)CCN1
Product: O=C(O[C@H](Cc1ccc(O)c(Br)c1)C(=O)N1CCN(C2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 7i from 100 mg (0.19 mmol) (R)-2-(3-bromo-4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 35.1 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CNCCO)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cccc(CNCCOC(=O)C(C)(C)C)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Next, in toluene (100 ml) were added 2-[(3-methoxyphenyl)methylamino]ethanol (8.1 g), pivaloyl chloride (10.8 g, 89.4 mmol), and pyridine (8.5 g, 107 mmol). The mixture was stirred at room temperature for 1 hour and further at 85° C. for 2 hours. After pyridine hydrochloride was removed by filtration, the filtrate was concentrated. The product was purified by silica gel chromatography to give 2,2-dimethylpropionic acid 2-[(3-methoxyphenyl)methylamino]ethyl ester as a colorless oily matter (yield: 10.4 g (78.4%)).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39]([O:41][C:42](=[O:46])[CH2:43][CH2:44]Br)[CH3:40]>CS(C)=O>[CH2:39]([O:41][C:42](=[O:46])[CH2:43][CH2:44][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:26][CH3:27])=[CH:10][CH:11]=3)[CH:25]=2)[CH:21]=[CH:22]1)[CH3:40]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Temperature: 90 °C
Yield: 70.9 %

Procedure:
To 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 mL), cesium carbonate (40 mg, 0.11 mmol, 1.1 eq.) and 3-bromo-propionic acid ethyl ester (0.014 mL, 0.11 mmol, 1.1 eq.). The reaction was stirred and heated at 90° C. for 17 hr. The reaction was diluted with dimethylsulfoxide, filtered, and purified by HPLC with a 50-100% acetonitrile in water gradient to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester as clear oil (33 mg, 73%). LC-MS (ES) calculated for C27H25F2NO4, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (82.9 mg, 70%)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[O:6][CH:7]=1.Cl.C[O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27]>>[F:20][C:2]([F:1])([F:21])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:15]([CH3:19])[C:16]([NH:27][C@@H:26]([CH3:28])[C:25]([OH:29])=[O:24])=[O:18])=[CH:13][CH:14]=2)[O:6][CH:7]=1
Reactant: COC(=O)[C@H](C)N
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)co2)cc1
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](C)c1ccc(Nc2nc(C(F)(F)F)co2)cc1)C(=O)O
Yield: 74.4 %

Procedure:
Following the same procedure described for 16 and starting from (2S)-2-(4-{[4-(trifluoromethyl)-1,3-oxazol-2-yl]amino}phenyl)propanoic acid (19) (0.118 g, 0.39 mmol) and L-alanine methyl ester hydrochloride (0.035 g, 0.39 mmol), after workup and methyl ester hydrolysis, pure compound 24 (0.112 g, 0.29 mmol) was isolated as pale yellow oil (75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of methyl 6-methoxynicotinate (3.00 g, 17.9 mmol) in tetrahydrofuran (10 mL) was added via an addition funnel over a period of 10 min to a cooled (0° C.) mixture of lithium aluminum hydride (817 mg, 21.5 mmol) in tetrahydrofuran (18 mL). The mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction mixture was poured into a solution of potassium sodium tartrate (10% w/v; 100 mL) and the resulting mixture was stirred at room temperature for 20 min. The mixture was filtered through a pad of Celite, washing with ethyl acetate. The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (magnesium sulfate), filtered and eluted through a silica plug using 40% ethyl acetate/hexanes to give (6-methoxy-pyridin-3-yl)-methanol (1.8 g, 72%) as a clear oil.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH3:25])=[N:17][S:16]2(=[O:34])=[O:33])=[CH:11][CH:10]=1>C1COCC1.C(OCCCC)CCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:9]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:12]([C:15]2([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH3:25])=[N:17][S:16]2(=[O:34])=[O:33])=[CH:11][CH:10]=1
Reactant: [Li]c1ccccc1
Reactant: C[C@H](NC1=NS(=O)(=O)C(C)(c2ccc(Br)cc2)C(C)(C)O1)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: C[C@H](NC1=NS(=O)(=O)C(C)(c2ccc(-c3ccccc3)cc2)C(C)(C)O1)c1ccccc1F
Reaction time: 0.5 h

Procedure:
Under inert gas, 5.56 ml of a 0.5 N zinc chloride solution in THF were cooled to −75° C., and 1.03 ml of a 1.8 N phenyllithium solution in dibutyl ether was added dropwise. The reaction solution was allowed to come to room temperature and stirred for 30 minutes. Then this solution was added to a solution of 87 mg of [5-(4-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-1-(2-fluorophenyl)ethyl]amine and 8 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium in 3 ml of THF. After stirring at 60° C. for 75 minutes, the conversion was checked by LCMS. Since it was incomplete, the reaction mixture was stirred at 60° C. for a further 2.5 hours. Since, by LCMS, no further conversion had taken place, another 30% of the above-described amount of the self-prepared solution of phenyllithium and zinc chloride was added, and the mixture was stirred at 60° C. for a further 60 minutes. Since, by LCMS, there was no further conversion, the reaction solution was concentrated by rotary evaporation. The residue was admixed with dichloromethane and water, and the organic phase was dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation, and the crude product was purified further in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (29.1 mg) with a molecular weight of 466.6 g/mol (C26H27FN2O3S); MS (ESI): m/e=467 (M+H+).
Reaction SMILES: [H-].[Na+].C1COCC1.C(O[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)C.[C:23](#[N:25])[CH3:24]>CCOCC>[F:21][C:18]([F:19])([F:20])[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([CH2:24][C:23]#[N:25])=[O:22]
Reactant: CC#N
Reactant: CCOC(=O)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 59.3 %

Procedure:
NaH (4.8 grams in a 50% oil dispersion) was placed in a 500 ml. 3-necked flask under an atmosphere of nitrogen and, after the addition of 80 ml. of THF, the mixture was heated to reflux. Next a solution of ethyl-3-(trifluoromethyl)benzoate (19 grams), acetonitrile, (5 grams) and THF (20 ml.) was added. Reflux was continued for 2 hours and then the reaction mixture was cooled and 250 ml. ether added. The organic layer was first extracted with 1 N NaOH, and then washed with brine and dried. Removal of the solvent afforded 11 grams of solid product, m.p. 58°-60° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4](N)[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (107 mmol) of 3-bromo-2-methylphenylamine are dissolved in 150 mL of aqueous 1.0M sulphuric acid and the mixture is cooled to 0° C. A solution of 8.9 g (129 mmol) of sodium nitrite in 20 mL of water is added slowly. The medium is stirred for 15 minutes at 0° C., and 50 mL of concentrated sulphuric acid are then added. The reaction medium is then heated at 100° C. for 1 hour and then cooled and diluted in water. After extraction with ethyl ether, the residue obtained is recrystallized from a heptane/dichloromethane mixture. A yellow solid is obtained (m.p.=89° C.; m=12.3 g; Y=61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13](O)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[OH:22].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([Cl:26])=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[OH:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)[nH]1
Yield: 119.7 %

Procedure:
A suspension of the product from Step 1 (1.24 g, 3.9 mmol) in dichloromethane (50 ml) was treated with oxalyl chloride (3.4 ml, 39 mmol) and 10 drops dimethylformamide. The suspension was then heated at reflux for 5 hours, cooled and concentrated under vacuum. The resultant residue was azeotroped with toluene then trituated with hexane to afford the title compound (1.56 g), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:14]([C:11]1[CH:12]=[CH:13][C:8]2[O:7][C:6]3[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=3[C:9]=2[CH:10]=1)=[O:15])[CH3:21]
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Reactant: CCN
Product: CCNC(=O)c1ccc2oc3c(c2c1)CC(N(C)C)CC3
Yield: 32.3 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol ethylamine, 0.0037 gm (33%) of the title compound were recovered.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C@@H:10](O)CC)=[S:7])(C)(C)[CH3:2]>Cl>[CH2:1]([NH:5][C:6]1[S:7][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:8]=1)[CH3:2]
Reactant: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=S)NC(C)(C)C
Agent: Cl
Product: CCNC1=NC(Cc2ccncc2)CS1
Temperature: 100 °C

Procedure:
A suspension of 4.2 g of N-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea in 40 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 100° C. for 20 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is chromatographed at atmospheric pressure on a column of silica gel (particle size 40-63μ; diameter 3.6 cm; height 24 cm), eluting with a dichloromethane/methanol mixture (98/2 by volume) and then with a dichloromethane/methanol mixture (97/3 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions, taken up in 30 cm3 of dichloromethane and basified with 1N sodium hydroxide. The organic phase is dried over magnesium sulphate, filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. 1.4 g of (+)-(4R,5R)-5-(ethyl-4-(4-pyridylmethyl)-4,5-dihydro-2-thiazolylamine are obtained in the form of a white solid melting at 124° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.83 (t, J=7.5 Hz: 3H); 1.43 (mt: 1H); 1.61 (mt: 1H); 2.70 (limiting AB: 2H); 3.40 (mt: 1H); 4.08 (mt: 1H); 6.28 (unresolved complex: 2H); 7.29 (broad d, J=5.5 Hz: 2H); 8.45 (broad d, J=5.5 Hz: 2H), (αD20=+166.9+/−2.4 at a concentration of 0.5% in methanol)].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.Cl>CO>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1
Reactant: COC(=O)Cc1ccc(-c2cccc3[nH]nc(N)c23)cc1
Agent: Cl
Solvent: CO
Product: Nc1n[nH]c2cccc(-c3ccc(CC(=O)O)cc3)c12
Yield: 81.2 %

Procedure:
A solution of Example 53A (140 mg) in 1:1 methanol/10% NaOH (1 mL) was stirred at room temperature for 2 hours and adjusted to pH 3 with 10% HCl. The resulting precipitate was collected by filtration to provide 108 mg of the desired product. MS (ESI(+)) m/e 268 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[Cl:1])[CH:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)ccc2c1Cl

Procedure:
A mixture of 1925 g. of 1-chloro-2-methoxynaphthalene, 80 g. of acetyl chloride, 400 g. of aluminum chloride and 2.5 liters of nitrobenzene are stirred for 60 hours at room temperature. The temperature mixture is then washed with dilute hydrochloric acid, dried over sodium sulfate and evaporated to yield 2-acetyl-5-chloro-6-methoxynaphthalene. The resulting acetyl product is added to a mixture of 39 g. of sulfur and 105 g. of morpholine and heated to about 150° C for 3 hours. The mixture is then added to 1 liter of concentrated hydrochloric acid and refluxed for 3 hours. The mixture is then cooled, diluted with 6 liters of ice-water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate and evaporated to yield 2-(5'-chloro-6'-methoxy-2'-naphthyl) acetic acid.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18](OC4C=CC=CC=4F)=[C:17]([O:29][CH3:30])[CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([S:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:17]([O:29][CH3:30])[CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1F
Reactant: Sc1ccccc1
Product: COc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Sc1ccccc1

Procedure:
Prepared according to a procedure analogous to that described for 3-cyclobutyl-1-[4-(2-fluoro-phenoxy)-3-methoxy-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine except using benzenethiol. 1H NMR (400 MHz, CDCl3)-6=1.99-2.11 (m, 1H), 2.13-2.26 (m, 1H), 2.45-2.55 (m, 2H), 2.57-2.69 (m, 2H), 3.75-3.85 (m, 1H), 3.97 (s, 3H), 5.44 (br. s., 2H), 6.82 (d, J=5.6 Hz, 1H), 7.00-7.08 (m, 3H), 7.17 (d, J=1.3 Hz, 1H), 7.34-7.43 (m, 3H), 7.45-7.51 (m, 2H). MS (ES+): m/z 402.96 (100) [MH+].
Reaction SMILES: [N:1]1([CH:10]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:11](O)=[O:12])C2C=CC=CC=2N=N1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=1[C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O.C(N(CC)CC)C.N>C(Cl)Cl.CN(C=O)C.CC(O)=O>[CH3:39][O:38][C:37]1[C:32]2[NH:31][C:11](=[O:12])[CH:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:1]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc(C(=O)c2ccccc2)c1N
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1NC(=O)C(NC(=O)OCc1ccccc1)N=C2c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a stirred suspension of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (1.08 g, 3.31 mmol) in CH2Cl2 (Ratio: 4.00, Volume: 20 mL) and DMF (5 drops) at room temperature was added oxalyl chloride (0.31 mL, 3.54 mmol). The reaction mixture was stirred at 0° C. for 20 min. The above solution was transferred to an addition funnel, then was added dropwise over 25 min to a cool (0° C.), stirred solution of (2-amino-3-methoxyphenyl)(phenyl)methanone, Intermediate A-1B (379.3 mg, 1.669 mmol) and triethyl amine (0.52 mL, 3.73 mmol) in CH2Cl2 (5 mL). The reaction mixture was removed from the ice bath after 30 min and stirred at room temperature for 1 h. The mixture was washed with saturated NaHCO3 and brine, then dried (MgSO4), filtered and partially concentrated to ˜10 mL. To this was added MeOH (40 mL) and the mixture was partially concentrated to 20 mL. Ammonia (2.0M in MeOH) (5.0 mL, 10.00 mmol) was added to the stirring methanolic solution. The mixture was stirred for 16 h. AcOH (20 mL) was added and the mixture was stirred at room temperature for 5 h. The reaction mixture was then concentrated, the residue was dissolved in CH2Cl2 and water, brought to pH ˜9-10 with 1M NaOH. The organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=1:1 heptane:DCM/EtOAc, REDISEP® SiO2 80 g, loaded as DCM solution). Fractions containing product were collected and concentrated to afford (benzyl 9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate, Intermediate A-1C (529.6 mg, 1.275 mmol, 76% yield)) as a pale yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 7.98 (1H, s), 7.55 (2H, d, J=7.0 Hz), 7.29-7.50 (8H, m), 7.10-7.19 (1H, m), 7.03-7.09 (1H, m), 6.94 (1H, dd, J=7.9, 1.1 Hz), 6.60 (1H, d, J=8.4 Hz), 5.34 (1H, d, J=8.4 Hz), 5.18 (2H, s), 3.97 (3H, s).