Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([OH:19])=[CH:17][C:16]=1[C:22]([CH3:25])([CH3:24])[CH3:23]>CO>[C:1]([C:5]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:2])[CH3:3].[C:22]([C:16]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:15]=1[O:14][CH3:13])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: COc1ccc(O)cc1C(C)(C)C
Solvent: CO
Product: COc1ccc(O)c(C(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
5.0 g of tert-butyl-hydroquinone, 40 cm3 of methanol and 1.0 g of cupric chloride are fed into the autoclave. The autoclave is purged with nitrogen and kept at 105° C. for 2.5 hours. On termination of the reaction, mixture analysis indicates the formation of 4.4 g of tert-butyl-hydroquinone monomethyl ether (BHA) (conversion 100%, selectivity 82%). The two BHA isomers (3-tert-butyl-4-hydroxyanisole and 2-tert-butyl-4-hydroxyanisole) are formed in a weight ratio of 99:1.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH2:32][CH3:33])[CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[Cl-].[NH4+]>O1CCCC1>[CH3:39][CH2:38][O:37][C:35]([C:24]1[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:31]2[C:26]([CH:25]=1)=[CH:27][CH:28]=[CH:29][C:30]=2[CH2:32][CH3:33])=[O:36]
Reactant: CCc1cccc2ccn(C(=O)OC(C)(C)C)c12
Reactant: CCOC(=O)Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(CC)c2n1C(=O)OC(C)(C)C
Reaction time: 0.83 h
Yield: 56.2 %

Procedure:
2,2,6,6-Tetramethylpiperidine (2.21 g, 15.6 mmol) was dissolved in 30 mL tetrahydrofuran and cooled down to −75° C. n-Butyllithium (9 mL, 14.3 mmol, 1.6M solution in n-hexane) was added while maintaining the temperature below −70° C. After 50 min., a solution of 3.2 g (13.0 mmol) 7-ethyl-indole-1-carboxylic acid tert-butyl ester in 15 mL tetrahydrofuran was added and the temperature again kept below −70° C. After 50 min., ethyl chloroformate (1.4 mL (14.3 mmol) was added and the temperature was allowed to rise to −50° C. After 1 h the reaction mixture was poured into 30 mL saturated aq. ammonium chloride solution and the phases separated. The aqueous phase was extracted once with 50 mL diethyl ether and the combined organic extractions were washed successively with saturated aq. ammonium chloride solution and water, dried over magnesium sulfate, filtered and evaporated. The crude reaction product was flash-chromatographed over silica gel (0.030-0.060 mm) with n-hexane/tert-butyl methyl ether (39/1) as eluant to give the product as a yellow oil (2.3 g, 56.2%). EI-MS: m/e=317.2 ([M])
Reaction SMILES: Cl[C:2]1[C:3]2[C:18]([CH3:19])=[CH:17][S:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:7]=1.[N:20]1([C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[CH2:25][CH2:24]2)[C:3]2[C:18]([CH3:19])=[CH:17][S:16][C:4]=2[N:5]=1
Reactant: COc1ccccc1-c1nc(Cl)c2c(C)csc2n1
Reactant: CC(C)COC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)c2c(C)csc2n1
Yield: 93.5 %

Procedure:
A solution of 4-chloro-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.1 g, 0.34 mmol), isobutyl piperazine-1-carboxylate (0.06 g, 0.34 mmol), and Et3N (0.096 mL, 0.68 mmol) in DMF (1.2 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.14 g, 47% yield). LC/MS: m/z 441.3 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])[C:5]=3[C:4]=2[CH:3]=1>CO.N.[Ni]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH2:18][NH2:19])[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1cccc(-n2cnc3cnc4ccc(Cl)cc4c32)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(-n2cnc3cnc4ccc(Cl)cc4c32)c1
Reaction time: 16 h

Procedure:
300 mg (0.98 mmol) of 3-(8-chloro-imidazo[4,5-c]quinolin-1-yl)-benzonitrile (Example 35) in 20 ml methanol/NH3 10% and 250 mg Raney-Ni are hydrogenated at rt for 5 h. The reaction solution is filtered on Hyflo® Super Cel diatomaceous earth and is evaporated to dryness. The title compound is crystallized from ethyl acetate-hexane to yield a grey powder. Drying is done for 16 h at 60° C. (high-vacuum). mp: 148-149° C.; MS: 309 (M++1); HPLC: tret=8.87 min (Grad 3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 62.8 %

Procedure:
A solution of 2-amino-pyridine (2 g, 21 mmol) and ethyl bromopyruvate (4.14 g, 21 mmol) in ethanol (31 mL) was stirred under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH==8) with saturated NaHCO3. The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was removed under pressure to afford 2.51 g of ethyl imidazo[1,2-a]pyridine-2-carboxylate (Yield: 62%) as an orange oil which can be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([F:17])[CH:3]=1.[CH3:18][Si:19]([CH3:48])([CH3:47])[C:20]1[CH:21]=[C:22]([CH:40]=[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1)[C:23](NC1C=CC(C=CC(OCC)=O)=C(F)C=1)=[O:24]>>[CH3:44][Si:43]([CH3:46])([CH3:45])[C:41]1[CH:40]=[C:22]([CH:21]=[C:20]([Si:19]([CH3:48])([CH3:47])[CH3:18])[CH:42]=1)[C:23]([NH:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([F:17])[CH:3]=1)=[O:24]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Reactant: CCOC(=O)/C=C(\C)c1cc(F)c(N)cc1F
Product: CCOC(=O)/C=C(\C)c1cc(F)c(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Yield: 46 %

Procedure:
BTMB (800 mg) and Compound 10a (869 mg) were reacted in the same manner as Compound 2b was synthesized. After the reaction was over, the reaction mixture was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (5% ethyl acetate/n-hexane) to obtain Compound 10b (674 mg, 46%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[OH-].[NH4+:23]>>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH2:23])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC[C@@H]1c2nncn2-c2cnc(N)nc2N1C1CCCC1
Yield: 36 %

Procedure:
A solution of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (500 mg, 1.64 mmol) in ammonium hydroxide (10 ml) was heated under microwave irradiation at 140° C. for 30 minutes. The solvent was removed under reduced pressure and cold water (5 mL) was added. The resulting light brown solid was filtered under vacuum and washed with cold water to give the title compound (170 mg, 36% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](O)[CH2:3][CH2:2]1.[N+:8]([C:11]1[CH:12]=[N:13][NH:14][CH:15]=1)([O-:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N+:8]([C:11]1[CH:12]=[N:13][N:14]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:15]=1)([O-:10])=[O:9]
Reactant: OC1CCOCC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a stirred solution of tetrahydro-2H-pyran-4-ol (1 equiv), 4-nitro-1H-pyrazole (1 equiv) and triphenylphosphine (1.2 equiv) in THF (1.0 M) was added diisopropyl azodicarboxylate (1.5 equiv) in THF (2.0 M) at 0° C. The mixture was stirred at room temperature overnight. The crude product was purified by silica gel chromatography (2.5% MeOH in DCM) to afford the desired product (23% yield) as a white solid. MS (ESI) m/z 198.1 [M+H]+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.CO.[NH2:38][C@H:39]([CH2:43][OH:44])[CH:40]([CH3:42])[CH3:41]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:38][C@H:39]([CH2:43][OH:44])[CH:40]([CH3:42])[CH3:41])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC(C)[C@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, oleic acid (1) (1.53 g, 5.33 mmol) was dissolved in 20 ml of dry pyridine (over KOH). To the solution TEA (0.74 ml, 5.33 mmol), DCC (1.1 g, 5.33 mmol), and NHS (0.55 g, 4.85 mmol) were added. The mixture was stirred at room temperature for overnight. After confirming the total conversion of the acid to the NHS intermediate using TLC (5% MeOH), L-Valinol (0.5 g, 4.85 mmol) was added and the mixture was stirred for additional 24 hours. After completion of the reaction (TLC: 100% Ethyl acetate), volatiles were removed under reduced pressure to dryness. The gum was dissolved in 5 ml DCM and the desired product oleoyl-valinol (10) was obtained using column chromatography (dichloromethane/ethyl acetate=1:1, v/v)). Colorless viscous oil (0.94 g, 46.8 yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][C:25]#[CH:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:22])[CH2:24][C:25]#[CH:26])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C#CCNC
Product: C#CCN(C)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Methyl-prop-2-ynyl-amine were converted to yield {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-prop-2-ynyl-amine as colorless oil, MS: 415 (MH+,1Br).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][O:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.N.O=P(Cl)(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][O:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]2)[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(C(N)=O)c(F)c2)CO1
Agent: N
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(C#N)c(F)c2)CO1

Procedure:
A solution of 29.5 g. trans-2-fluoro-4-(5-pentyl-1,4-dioxan-2-yl)-benzamide (obtainable from the acid chloride and NH3) in 500 ml. DMF is mixed dropwise at 50°, while stirring, with 65 g. POCl3. After a further one hour stirring, one pours on to ice, works up as usual and obtains trans-2-fluoro-4-(5-pentyl-1,4-dioxan-2-yl)-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]([OH:6])[C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)c2cccc(Cl)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of (R)-tert-butyl 2-(3-chlorobenzoyl)morpholine-4-carboxylate (5.5 g, 16.9 mmol) in MeOH (50 mL), NaBH4 (5.14 g, 135 mmol) was added in portions. The mixture was stirred overnight and water (50 mL) was added, The mixture was concentrated in vacuo until MeOH was removed. The aqueous residue was extracted with EtOAc. The organic extracts were washed with brine and dried over Na2SO4. The crude product was purified by chromatography to afford (R)-tert-butyl 2-((S)-(3-chlorophenyl)(hydroxy)methyl)morpholine-4-carboxylate (4.3 g, 78%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:13])OCC)[CH:6]=[CH:7][CH:8]=1.[NH3:14]>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([NH2:13])=[NH:14]
Reactant: N
Reactant: CCOC(=N)c1cccc(Cl)c1
Agent: Cl
Product: N=C(N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 18-mL vial was charged with ethyl 3-chlorobenzenecarboximidate hydrochloride (450 mg, 2 mmol, 1 eq.) and NH3 (2N in ethanol, 12 ml, 24 mmol, 12 eq.). The resulting mixture was stirred at rt overnight. The volatile material was removed under reduced pressure and the product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:29][CH2:30][O:31][CH3:32]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][CH2:30][O:31][CH3:32])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: COCCBr
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cc2cccc3ccccc23)c2ccccc2n1CCOC
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (170 mg, from Exp. 64.2.) in dimethylformamide (1.0 ml) was added NaH (1.3 eq.), the mixture was stirred at 22° C. for 30 min. 1-Bromo-2-methoxy-ethane (99 mg) was added, the mixture was stirred for 17 h and partitioned between aqueous NH4Cl and AcOEt. The organic layer was dried, evaporated and the residue was chromatographed on silica (n-heptane/AcOEt, 20:1) to give 1-(2-methoxy-ethyl)-3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white semisolid. MS: 358.1 ([M−H]−).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH:22]([CH3:23])[CH3:24])=[N:20][O:21][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3onc(C(C)C)c23)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4onc(C(C)C)c34)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-amino-N-(6-{[3-(1-methylethyl)-1,2-benzisoxazol-4-yl]oxy}-3-pyridinyl)butanamide (Intermediate 44) was dissolved in dichloromethane (1.0 ml) and TEA (3 μL, 0.022 mmol) was added. The reaction mixture was cooled down to 0° C. and triphosgene (0.6 mg, 1.98 μmol) was added and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was quenched with water and water was removed by addition of sodium sulphate. The organic phase was pipetted off and evaporated and the residue obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAc (from all 1/0 to 7/3, then 7/3, then from 7/3 to 1/1, then 1/1, then 0/1) to afford the title compound (1 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[CH:9]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CO>[Cl:18][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:32][C:31]3[CH:30]=[CH:29][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:34][CH:33]=3)[N:7]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=1
Reactant: Cc1cnc(Cl)nc1-c1cc(Cl)cc(C(F)(F)F)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cc(Cl)cc(C(F)(F)F)c1
Yield: 76 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-5-(trifluoromethyl)phenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 76% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.79 (d, 2H, J=7.8 Hz), 7.69 (s, 1H), 7.55 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J=8.6 Hz), 3.47 (s, 2H), 2.50 (bs, 8H), 2.31 (s, 3H), 2.25 (s, 3H); MS (ESI): 476.3 [M+H]+, 238.7 [M+2H]2+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23](=[O:44])[NH:24][CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:44])[NH:24][CH2:25][C:26]1([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])=[CH:33][CH:34]=2)[CH2:27][CH2:28]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 52.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (830 mg, 2.7 mmol) was reacted with tert-butyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methylcarbamate (1.5 g, 4.0 mmol) to afford the desired product (670 mg, 52%) as a light brown solid: ESI MS m/z 477 [C27H28N2O4S+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1.C(OC([NH:42][C:43](N1C=CC=N1)=[NH:44])=O)C1C=CC=CC=1>O1CCCC1>[NH:1]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1)[C:43]([NH2:44])=[NH:42]
Reactant: NCCCOc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Solvent: C1CCOC1
Product: N=C(N)NCCCOc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 4.6 %

Procedure:
2-[3-(3-Aminopropoxy)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.2 g) and N-(benzyloxycarbonyl)-1H-pyrazol-1-carboxamidine (0.55 g) were suspended in tetrahydrofuran (2.5 mL), and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (4 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 40° C. under a hydrogen atmosphere for 2 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (0.01 g).
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:19][O:18][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)[CH:4]=[O:20]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(C=O)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
To a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (1.5 g, 5.1 mmol) in anhydr CH2Cl2 (12 mL) and anhydr toluene (6 mL) at −78° C. was added a solution of DIBALH (1 M in hexanes, 7.8 mL, 7.8 mmol) dropwise over 5 min. After stirring at −78° C. for 1 hr, the reaction was quenched with the dropwise addition of EtOAc. The mixture was stirred 2 min then Et2O and saturated aqueous NH4Cl were added and the mixture was warmed to room temp. After stirring for 30 min the mixture was diluted with EtOAc and H2O and the layers separated. 10% Aqueous potassium sodium tartrate was added to the aqueous layer and it was extracted with EtOAc/Et2O. The combined organics were washed with saturated aqeuous NH4Cl and dried over Na2SO4 to give 2-methoxy-2-(4-morpholinophenyl)acetaldehyde as a yellow oil (1.27 g). The product was used in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:5][CH:6]=1.[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19]>>[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@@H:22]([C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[C:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:5][CH:6]=2)=[CH:27][CH:28]=1)[OH:33])=[O:19]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cs1
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cs1
Yield: 20.3 %

Procedure:
The compound is prepared from tert-butyl ((4-bromothiophen-2-yl)methyl)-carbamate (132 mg, 0.45 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (200 mg, 0.45 mmol) in a manner analogous to Example 2 to give the tile compound (45 mg): 1H-NMR (400 MHz, CDCl3) 1.47 (s, 9H), 2.73 (bs, 1H), 4.26-4.38 (m, 1H), 4.39-4.52 (m, 2.5H), 4.53-4.61 (m, 1H), 4.65-4.72 (m, 0.5H), 4.87-5.03 (m, 1H), 5.12 (d, J=4.0 Hz, 1H), 5.87 (s, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.20 (s, 1H), 7.32 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.54 (m, 2H).