Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:8]=2)[N:3]=1.O=S(Cl)[Cl:27]>C(Cl)Cl>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:27])=[O:20])[CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCN1Cc2cc(Oc3cccc(C(=O)O)c3)ccc2N=C1N
Solvent: ClCCl
Product: CCCN1Cc2cc(Oc3cccc(C(=O)Cl)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoic acid (0.0009 mol) in SOCl2 (2 mL) and DCM (10 mL) was stirred for 2 hours at room temperature and then the solvent was evaporated. The obtained residue was stirred in toluene and the solvent was evaporated again to yield the title compound as a residue.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>O>[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:11]
Reactant: C1CCNC1
Reactant: O=C(Cl)CCCCl
Solvent: O
Product: O=C(CCCCl)N1CCCC1
Reaction time: 8 h
Yield: 51 %

Procedure:
To a stirred and cooled (ice bath) solution of 71.12 parts of pyrrolidine in 210 parts of petroleumether were added dropwise 70.5 parts of 4-chlorobutanoyl chloride at a temperature below 15° C. Upon completion, stirring was continued overnight at room temperature. Water was added. The product was extracted with dichloromethane. The extract was separated, dried, filtered and evaporated. The residue was distilled at 266 Pa bp. 137° C., yielding 45 parts (51%) of 1-(4-chloro-1-oxobutyl)pyrrolidine (int. 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])C#N)[C:3]=1[CH3:21].P(=O)(O)(O)[OH:23]>O>[OH:23][C:2]1[C:3]([CH3:21])=[C:4]([CH2:9][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1cc(C)c(C(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Reactant: O=P(O)(O)O
Solvent: O
Product: Cc1cc(C)c(Cc2nc(C)nc(O)c2C)c(C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 6-chloro-2,5-dimethylpyrimidin-4-yl-(2,4,6-trimethylphenyl)-acetonitrile (1.5 g, 5.0 mmol) and 60 ml of 85% phosphoric acid was heated at reflux for 2 hours. The mixture was cooled at rt and diluted with water and extracted with chloroform. The organic layer was washed with brine, dried and concentrated to give 1.21 g (95%) of the title compound as a white solid, mp 260-262° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19]C3C=CC=CC=3)[C:12]=2[C:26]#[N:27])=[CH:7][CH:6]=1.[S-2].[Na+].[Na+].Cl>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([SH:19])[C:12]=2[C:26]#[N:27])=[CH:9][CH:10]=1
Reactant: N#Cc1cnc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: N#Cc1cnc(S)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.1 g (0.268 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-(phenylthio)pyridine-3,5-dicarbonitrile (Example 47A) was initially charged in 1 ml of DMF. 73 mg (0.937 mmol) of sodium sulfide were added, and the mixture was then stirred at 80° C. for 2 h and stirred further at RT overnight. 20 ml of 1N hydrochloric acid were added, and the residue was filtered off and washed thoroughly with water.
Reaction SMILES: O.Cl[CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11].O.[SH-:13].[Na+]>CN(C=O)C>[SH:13][CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11]
Reactant: O=S(=O)([O-])CC(O)CCl
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)([O-])CC(O)CS
Yield: 172.6 %

Procedure:
To sodium 3-chloro-2-hydroxypropanesulfonate hydrate (2.0 g), sodium hydrosulfide hydrate (0.42 g) was added in 10 mL DMF. The mixture was refluxed overnight. When the reaction mixture was cooled down, white solid was isolated, rinsed with ether and acetone to obtain 1.9 g crude sodium 3-mercapto-2-hydroxypropane sulfonate. The crude product was dissolved in water and preferentially precipitated the desired product by adding acetone. The precipitated product was then filtered and dried under vacuum to get 1.04 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C>[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[CH2:22][CH2:21]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Reactant: Brc1cncnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc([C@H]2CCCC[C@H]2N2CCC(Nc3cncnc3)CC2)cc1
Temperature: 70 °C
Yield: 20.6 %

Procedure:
The title compound, MS (ISP): m/e=446.4 (M+H+), was prepared as for example 209, steps (A) to (C). Step (B) was performed using 5-bromo-pyrimidine as follows: A suspension of (+/−)-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-amine (1.46 g, 5.65 mmol) in toluene (35 ml) was degassed with a flow of argon for 10 minutes. Tris-(dibenzylideneacetone)dipalladium chloroform complex (179 mg, 0.17 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP, 108.0 mg, 0.17 mmol), sodium tert-butoxide (0.660 g, 6.87 mmol) and 5-bromopyrimidine (0.720 g, 4.53 mmol) were added under argon. The flask was sealed and warmed to 70° C. for 3 hours. The mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and washed three times with saturated sodium chloride solution. The organic phase was dried with sodium sulphate and evaporated, yielding a red oil. Purification was achieved by flash chromatography (dichloromethane/methanol/25% NH3 90:10:1). (+/−)-[cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-yl]-pyrimidin-5-yl-amine (0.392 g, 20.6%) was obtained as an orange foam, MS (ISP): m/e=337.3 (M+H+). This was reacted with 5-methyl-isoxazole-3-carbonyl chloride in step (C).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[NH:8][C:7]=2[CH:22]=1.[CH2:31](Br)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[N:8]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:7]=2[CH:22]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Product: COc1ccccc1-c1cc2c(cc1OC)N(CCc1ccccc1)C(=O)CN=C2c1cccc(C#N)c1
Yield: 87 %

Procedure:
Prepared from 3-[8-methoxy-7-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile Example 10 using the same method described for Example 35 using phenethyl bromine instead of hexyl bromine. The title compound (110 mg) was obtained as a white solid, (yield=87%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=O)[CH2:7]1)=[O:5].[BH4-].[Na+].[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([NH:22][CH2:21][CH2:20][NH2:23])[CH2:8][CH2:7]1)=[O:5]
Reactant: NCCN
Reactant: O=C1CC(C(=O)c2ccc(F)cc2F)CCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: NCCNN1CCC(C(=O)c2ccc(F)cc2F)CC1
Yield: 38 %

Procedure:
A solution of 4-(2,4-difluorobenzoyl)piperidinone (1.50 g, 6.27 mmol) in benzene (40 mL) and ethylenediamine (4.0 mL) was refluxed for 6 hours. The resulting mixture was concentrated to a residue which was dissolved in MeOH (30 mL). The mixture was cooled (0° C.) and NaBH4 (1.0 g, 26.4 mmol) was slowly added. After stirred for an hour, the mixture was concentrated and quenched with 1 N NaOH (50 mL). The mixture was extracted with CH2Cl2 (5×20 mL), dried (K2CO3), and was concentrated. The residue was purified by flash chromatography (CHCl3—MeOH-2 M NH3 in MeOH 100:10:2 to 100:20:5) to afford the product as an pale yellow solid (670 mg, 38%).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>C(#N)C>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][O:10][C:9]1[C:4]([CH2:3][OH:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1ncccc1O
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ncccc1OCCOC1CCCCO1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A suspension of 85% pure 2-(hydroxymethyl)pyridin-3-ol hydrochloride (24.9 g, 130 mmol) and potassium carbonate (60 g, 434 mmol) in acetonitrile (200 mL) was heated at reflux for 15 minutes after which 2-(2-bromoethoxy)tetrahydro-2H-pyran (32.9 g, 160 mmol) was added in one portion and the heating was continued overnight. Solids were filtered off and the solvent was removed under reduced pressure and the resulting oil was chromatographed on a column of silica (100 mm, i.d.=60 mm) with CHCl3 as eluent followed by CHCl3/MeOH/NH4OH (95:5:0.2) to give 28.4 g (93%) of the title compound as a light brown oil. HRMS m/z calcd for C13H19NO4 (M)+ 253.1314. found 253.1326.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Li]CCCC.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of 5-fluoro-1H-indole (2.5 g, 18.52 mmol) and chlorotriisopropyl-silane (3.92 g, 20.4 mmol) in anhydrous THF (75 mL) at −78° C. was added dropwise a solution of n-BuLi in THF (1.6 mol/L, 12.7 mL, 20.37 mmol) at a rate to maintain the internal reaction temperature below −70° C. After the addition was completed, the mixture was stirred at −78° C. for 1 h and then poured into water (250 mL), extracted with DCM (100 mL×3), and concentrated in vacuo to afford 5-fluoro-1-(triisopropylsilyl)-1H-indole as a yellow oil (5.27 g, 97.6%). MS (ESI): m/z=292.3 [M+1]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:15]([C:16]#[N:17])([C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
Prepare by the method of example 1.1.2 using 4-(tert-butyldimethylsilyloxy)-phenyl-acetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[C@@H:15]([C:16]=2[CH:17]=1)[CH2:14][CH2:13][CH2:12][N:11]3[C:18]([C:20]1[CH:28]=[CH:27][C:23]2[NH:24][CH:25]=[N:26][C:22]=2[CH:21]=1)=[O:19])=[O:4].COC(C1C=CC2[C@@H]3[C@@H](N(C(C4C=CC5NC=NC=5C=4)=O)CCC3)CC=2C=1)=O>>[NH:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:18]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:15]4[C:16]5[CH:17]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=5[CH2:9][C@H:10]34)=[O:19])=[CH:21][C:22]=2[N:26]=[CH:25]1
Reactant: COC(=O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Agent: COC(=O)c1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: O=C(O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Yield: 4 %

Procedure:
The title compound is prepared from a ca. 1:1 mixture of cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid methyl ester and cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-7-carboxylic acid methyl ester following a procedure analogous to that described in Example 35 and separated from Example 99 by HPLC on reversed phase (MeCN/H2O). Yield: 4% of theory; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [N:1](OC(C)(C)C)=O.[NH2:8][C:9]1[C:10]2[C:36]([CH3:41])([C:37]([NH:39][NH2:40])=[O:38])[C:35](=[O:42])[NH:34][C:11]=2[N:12]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[N:16]=2)[N:14]=1.C(O)(C(F)(F)F)=O>C1COCC1>[NH2:8][C:9]1[C:10]2[C:36]([CH3:41])([C:37]([N:39]=[N+:40]=[N-:1])=[O:38])[C:35](=[O:42])[NH:34][C:11]=2[N:12]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:30])([F:29])[F:31])[N:16]=2)[N:14]=1
Reactant: CC(C)(C)ON=O
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C(=O)N=[N+]=[N-])C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 0 °C

Procedure:
t-Butyl nitrite (0.34 mL, 2.89 mmol) was added dropwise to a THF (3.5 mL) solution containing the intermediate from Step A above (300 mg, 0.578 mmol) and TFA (50 μL, 0.636 mmol) cooled to 0° C. After 50 min. the solution was carefully concentrated in vacuo (temperature <30° C.) to give the title compound as a solid which was used without further purification. m/z 502.0 (M−N2+H).
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[F:18])(O)=[O:2].S(Cl)([Cl:21])=O.CN(C=O)C>ClCCl>[F:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[N:8]1[CH2:7][CH2:6][O:5][CH2:4][C:1]1=[O:2])[C:13]([Cl:21])=[O:14]
Reactant: O=C(O)COCCNc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCOCC2=O)c(F)c1

Procedure:
Prepared analogously to Example 41c from 4-(2-carboxymethoxy-ethylamino)-3-fluoro-benzoic acid and thionylchloride in dichloromethane with DMF.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C(=O)C(C)(C)C)[CH:5]=[C:4]([CH3:15])[C:3]=1[NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.[OH-].[Na+].CO>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:15])[C:3]=1[NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: Cc1cc(OC(=O)C(C)(C)C)cc(Br)c1NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(O)cc(Br)c1NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
N-(2-bromo-6-methyl-4-pivaloyloxyphenyl) 3-nitrobenzamide and an aqueous solution of sodium hydroxide were added to methanol, and the resulting mixture was stirred at 70° C. for 3 hours. The solvent was removed under a reduced pressure to obtain a residue. The resulting residue was dissolved in ethyl acetate, washed with aqueous 2N hydrochloric acid solution, and then dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to obtain N-(2-bromo-6-methyl-4-hydroxyphenyl) 3-nitrobenzamide. Then, the desired title product was prepared according to the conditions as described in Example 1-3 (Yield: 97%).
Reaction SMILES: [OH:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([NH2:10])=[N:6][C:7]=1[CH2:8][CH3:9].O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][OH:19]>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([NH2:10])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N)nc(N)c1O
Reactant: OCCCBr
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(N)nc(N)c1OCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-hydroxy-6-ethyl-2,4-diaminopyrimidine (6) (3 mmol) and lithium hydroxide monohydrate (6 mmol) in N,N-dimethylformamide (DMF) (10 ml) was stirred at room temperature for 2 hours under nitrogen. 3-Bromo-1-propanol (3 mmol) was added and left stirring at room temperature for 10 hours. Removal of DMF gave the crude product, further purified by crystallization with water to yield the pure 5-(3′-hydroxypropoxy)-6-ethyl-2,4-diaminopyrimidine (7).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13]N2C3C=CC=CC=3N=C2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]1([CH:29]=NC2C=CC=CC=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:23]1([C:29]#[C:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 73 %

Procedure:
To potassium t-butoxide (5.6 g, 50 mmol) in DMF (40 mL) at 75° C. was added N-(phenylmethyl)-1H-benzimidazole (2.08 g, 10 mmol) and N-(phenylmethylene)benzenamine (1.81 g, 10 mmol) dissolved in DMF (10 mL). After 5 hours the solution is poured into ice-cold water (150 mL), extracted with CHCl3 (3×50 mL) and chromatographed (PE). Diphenylacetylene was obtained in 73 % yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([Br:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:58][C:55]1[N:56]=[CH:57][C:52]([NH:51][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)=[N:53][CH:54]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (200 mg, 0.56 mmol) and triphenylphosphine (195 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-bromopyrazine (200 mg, 1.12 mmol, prepared according to Tetrahedron 1988, 44, 2977-2983) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate eluted to 4/6 hexanes/ethyl acetate) afforded N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (120 mg, 42%) as an off-white foam: [α]23589=−24.6° (c=0.50, chloroform); EI-HRMS m/e calcd for C20H21BrClN3O4S (M+Na)+ 536.0017. found 536.0022.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH:16]([OH:18])[OH:17].C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:16]([OH:18])[OH:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: OBO
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The 3-benzyloxybromobenzene of formula IV is converted to the boronic acid derivative by dissolving in THF and adding one equivalent of n-butyllithium at -78° C. After stirring at -78° C. for approximately 30 minutes, one equivalent of triisopropyl borate is added and the reaction is slowly warmed to room temperature, followed by acidification with aqueous hydrochloric acid to give a 3-benzyloxybenzene boronic acid compound of formula V. ##STR7##
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[NH2:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[N:4]=1
Reactant: Nc1nc(Cl)ncc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(N)n2)CC1
Yield: 62.8 %

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2-chloropyrimidin-4-amine (8.0 g, 40 mmol), N,N-diisopropylethylamine (16.0 g, 120 mmol) and tert-butyl piperazine-1-carboxylate (11.0 g, 60 mmol). The resulting mixture was heated at reflux overnight. Work-up: the solvent was evaporated. The residue was re-crystallized from ethanol to afford 9.0 g (65%) of the product as a white solid. MS m/z: 358 (M+H+).
Reaction SMILES: O[Li].O.C([C:6]1([C:22]([O-:24])=[O:23])[CH2:21][N:9]2[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C:8]2=[N:7]1)C>CO.O>[C:17]([O:16][C:14]([N:12]1[CH2:11][CH2:10][N:9]2[CH:21]=[C:6]([C:22]([OH:24])=[O:23])[N:7]=[C:8]2[CH2:13]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCC1(C(=O)[O-])CN2CCN(C(=O)OC(C)(C)C)CC2=N1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
LiOH.H2O (8.8 mmol, 4.0 equiv.) was added at 0° C. to a solution of 7-tert-butyl 2-ethyl-5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (2.2 mmol, 1.0 equiv.) in methanol/water (2.5:1, 35 ml), and the mixture was then stirred for 2 h at 25° C. When the reaction was complete (TLC monitoring), the methanol was removed in vacuo, the residue was diluted with water (40 ml), and extraction with ethyl acetate (2×40 ml) was carried out. The aqueous phase was then adjusted to pH 2-3 with 1N HCl solution, and the resulting solid was filtered out. The solid was taken up in toluene, and the solvent was then removed in vacuo (2×) to yield the desired product in the form of a white solid. Yield: 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([CH:19]=[O:20])=[CH:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chlorobenzo[b]thiophene (6.14 g) in THF (120 ml) was added n-BuLi (1.6 M solution in hexane, 27.3 ml) at −78° C., and the mixture was stirred for 2 hours. To this mixture was added DMF (8.5 ml), and the mixture was stirred for 1 hour at −78° C. to −30° C. The reaction was quenched by the addition of water and allowed to warm to room temperature. The organic layer was separated, diluted with ethyl acetate, washed with 10% citric acid solution, brine, dried over MgSO4, and concentrated. The residue was titurated with diisopropylether to give the titled compound as colorless crystals (5.92 g).