Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[N:43][CH:42]=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: Clc1cnccn1
Product: COc1ccc(CC2c3cc(Oc4cnccn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-pyrazine
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[C:34]([F:37])([F:36])[F:35])=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[C:34]([F:35])([F:37])[F:36])=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F)NC1CNC1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F)NC1CN(C2CCC(O)(c3nccs3)CC2)C1

Procedure:
The title compound was prepared as white solids from reductive amination of 4-hydroxy-4-thiazol-2-yl-cyclohexanone, as prepared in Example 40 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-2,5-bis-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [K].C(O)C.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:16][C:17]1[CH:22]=[C:21]([C:23](=[N:25]O)[CH3:24])[CH:20]=[CH:19][N:18]=1.Cl.[C:28](=[NH:33])(OCC)[CH3:29]>C1(C)C=CC=CC=1.C1CCCCC1.CC(C)=O.CO>[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[N:25]=[C:28]([CH3:29])[NH:33][CH:24]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(=NO)c1ccnc(C)c1
Reactant: CCOC(C)=N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: Cc1cc(-c2c[nH]c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 570 mg. (14.2 mmoles) of potassium metal dissolved in 10 ml. of absolute ethanol was added a mixture of 4.33 g. (14.2 mmoles) of 2-methyl-4-acetylpyridine oxime tosylate in 20 ml. of absolute ethanol and the resulting mixture stirred at room temperature for 1.5 hours. The reaction was quenched with 100 ml. of ether and the potassium tosylate removed by filtration. Gaseous hydrogen chloride was bubbled into the filtrate for 5 minutes and the solution was concentrated. The residue was dissolved in 50 ml. of water and the solution was made basic with solid potassium carbonate. The aqueous was extracted with (5×20 ml.) chloroform and the combined organic extracts dried and concentrated to dryness giving an oil. The residual oil was dissolved in 25 ml. of methanol, 1.75 g. (14.2 mmoles) of ethyl acetimidate hydrochloride was added and the mixture was heated to reflux for 1.5 hours. The mixture was concentrated and the residue taken up in 25 ml. of concentrated hydrochloric acid. The acid solution was heated on a steam bath for one hour, then allowed to stir at room temperature for 18 hours. The mixture was made basic with solid potassium carbonate and was extracted with (2×50 ml.) chloroform and (1×50 ml.) ethyl acetate. The combined extracts were dried and evaporated leaving an oil which solidified on trituration with a toluene/cyclohexane/acetone mixture, 530 mg. (22%), m.p. 115°-117° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2ncccc2c1
Reaction time: 20 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (97 mg, 0.241 mmol), 6-aminoquinoline (50 mg, 0.347 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water was added to induce precipitation. The precipitate was collected, and dried on vacuum to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(quinolin-6-ylamino)pyrazine-2-carbonitrile as a solid. The solid 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(quinolin-6-ylamino)pyrazine-2-carbonitrile was dissolved in EtOH (4 mL) and DMSO (2 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (26 mg). MS 414.2 (M+H); UV 200.0, 263.4, 296.0, 356.1 nm; t 0.335 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:20])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:20])[N:14]([CH2:15][C:16]([CH3:18])([CH3:19])[OH:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CC(C)(C)O)CCCC3
Reaction time: 120 h

Procedure:
Platinum (IV) oxide (2.3 g) was added to a solution of 4-amino-α,α,2-trimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (10 g, 32 mmole, U.S. Pat. No. 5,266,575 Comparative Example C1) in trifluoroacetic acid (200 mL). The mixture was hydrogenated at 50 psi (3.44×105Pa) for 5 days. The catalyst was removed by filtration. The filtrate was concentrated under vacuum. The residue was diluted with water then combined with aqueous 10% sodium hydroxide. This mixture was stirred for one hour. A precipitate was isolated by filtration and dried to provide 9.7 g of 4-amino-α,α,2-trimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol as solid, m.p. 290°-292° C. Analysis: Calculated for C15H22N4O: % C, 65.67; % H, 8.08; % N, 20.42; Found % C, 65.45; % H, 7.68; % N, 20.52.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([I:23])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([I:23])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])(=[O:17])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1I
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(I)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 133.1 %

Procedure:
3-(3-chloro-5-iodo-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (922 mg) was dissolved in N,N-dimethylformamide (6 mL), and lithium chloride (421 mg) was added to the solution, and then the mixture was stirred at 120° C. for 2.5 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.19 g) as a brown oily substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)N=CC)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:25][C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O.O>C(O)(=O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]3[C:17]4[C:22](=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:26]3[CH3:25])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A mixture of acetaldehyde N1 -(7chloroquinazolin-4-yl)-p-methoxyphenylhydrazone hydrochloride (25g.) and laevulinic acid (50g.) in acetic acid (120ml.) was heated under reflux for 1-2 hours. The dark red mixture was then added to water (1.5 1.). The solid obtained was separated by filtration and dissolved in a mixture of water (50ml.) and 5N-aqueous ammonium hydroxide solution (50ml.). The solution was extracted with ether (3 × 50ml.) and the aqueous layer acidified with acetic acid to pH4. The mixture was then extracted with ethyl acetate (3 × 50ml.) and the extracts washed with water (30ml.) and then with saturated sodium chloride solution (30ml.) before being dried (MgSO4). Evaporation of the solvent gave a dark brown syrup which crystallised on addition of methanol (40ml.) to give 1-(7-chloroquinazolin-4-yl)5-methoxy-2-methylindol-3-ylacetic acid as a yellow solid, m.p. 205°-208° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14]Cl.[OH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][OH:16]
Reactant: O
Reactant: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Product: O=c1cc(CO)c2cc(Br)c(O)cc2o1
Yield: 98 %

Procedure:
A suspension of 291.7 mg (1.008 mmol) of compound 11 in water (50 mL) was refluxed for 14 hours. The resulting solution was cooled and evaporated to give 268.7 mg (0.9913 mmol, 98% yield) of compound 14 as a solid, pure enough to use in the next step without further purification. 1H NMR (CD3OD) δ 7.83 (1H, s), 6.86 (1H, s), 6.40 (1H, s), 4.78 (2H, s).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[C:1]1([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(C2=CCCCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(C2=CCCCCCC2)cc1
Temperature: 180 °C

Procedure:
80 Grams of p-(1-cyclooctenyl)-anisol and 175 g of pyridine-hydrochloride are thoroughly mixed and heated for 4 hours under nitrogen to 180° C. The mixture is cooled, treated with water and extracted with benzene. The benzene extracts are shaken with 3×100 ml of N-sodium hydroxide solution. The alkaline phase is acidified with 2N hydrochloric acid and extracted with ether. The ether solution is dried over sodium sulphate and evaporated. The residue is recrystallised from benzene-petroleum ether to yield the p-(1-cyclooctenyl)-phenol (m.p. 95°-97° C).
Reaction SMILES: C(C1N=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24]C2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C(O)=O.C1C2(CCCN2)CO1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C:27]32[CH2:24][O:25][CH2:26]3)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNC2(C1)COC2
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCCC23COC3)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-5-azaspiro[3.4]octane oxalate and isolated as white solid (8.4 mg, 43%). MS(m/e): 413.4 (MH+).
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:11]>C1COCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]([OH:11])([CH3:9])[CH2:7][C:6]#[N:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CC#N
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(CC#N)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dry THF (15 mL) was cooled to −78° C. and 2.5M n-BuLi (5.18 mL, 2.0 equiv.) was added. A solution of acetonitrile (680 μL, 2.0 equiv.) in dry THF (2 mL) was added dropwise over 2 min. The mixture was stirred at −78° C. for 1 h. A solution of 3-chloroacetophenone (835 μL, 6.468 mmol) in dry THF (2 mL) was added dropwise over 2 min. 30 min. The mixture was stirred at −78° C. for 30 min. and was warmed to rt slowly. After being stirred at rt for 15 min., the mixture was quenched with water (10 mL), diluted by ether (20 mL), washed with 2% aq HCl (15 mL). The aqueous layer was extracted with ether (2×10 mL). The combined organic layers were washed with satd aq NaHCO3 (5 mL) and brine (10 mL), and dried over Na2SO4. After filtration and concentration, the crude product (1.4 g, quant. yield) was used for next step without further purification. LC-MS Method 1 tR=1.40 min., m/z=219, 221 (M+Na).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][C:26]([F:25])([F:36])[F:37])=[CH:29][CH:30]=2)[C:11]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1Cc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared from tert-butyl 4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate and 4-(trifluoromethoxy)benzylbromide essentially following the procedure described in Example 3, Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(F)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1C(Cl)=Nc1ccnc(Cl)c1F
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-N-(2-chloro-3-fluoro-pyridine-4-yl)-6-fluorobenzamide (600 mg, 2 mmol) and thionyl chloride (5 mL) was heated under reflux for 16 hours then cooled to ambient temperature. The reaction mixture was diluted with toluene (6 mL) and concentrated to dryness under reduced pressure to give the desired compound as a brown oil (650 mg, quant. yield). 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J=5.1 Hz, 1H), 7.44 (td, J=8.3, 5.6 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.16 (t, J=8.7 Hz, 1H), 6.97 (t, J=5.1 Hz, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[N:35][C:34]([O:33][CH3:32])=[N:39][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: COc1ncc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cn1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-methoxypyrimidine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (11%).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10]CC=C)=[CH:8][C:7]([O:14]CC=C)=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:3])[CH3:2].C([O-])=O.[NH4+].Cl>O1CCOCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:14])=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:3])[CH3:2]
Reactant: C=CCOc1cc(CC(=O)OC)c(C(C)=O)c(OCC=C)c1
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: Cl
Agent: O=C[O-]
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(O)cc(O)c1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
Methyl 2-acetyl-3,5-diallyloxyphenylacetate (22 g, 72 mmol) obtained in Example 5, Step 2 was dissolved in 1,4-dioxane (0.20 L). To the solution were added ammonium formate (18 g, 0.29 mol) and bis(triphenylphosphine)palladium (II) dichloride (2.5 g, 3.6 mmol), followed by stirring for 8 hours under heating and reflux. After cooling to room temperature, the reaction mixture was made acidic by addition of 3 mol/L hydrochloric acid (0.20 L) and then concentrated under reduced pressure. The resulting residue was extracted with a mixed solvent of ethyl acetate and methanol (ethyl acetate/methanol=4/1, 0.20 L×4). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain methyl 2-acetyl-3,5-dihydroxyphenylacetate (6.2 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH2:14][CH3:15])=[CH:6][C:5]=1[NH2:16].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>O>[CH3:20][N:21]([CH:23]=[N:16][C:5]1[CH:6]=[C:7]([O:13][CH2:14][CH3:15])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:17])[CH3:22]
Reactant: COC(OC)N(C)C
Reactant: CCOc1cc(N)c(C(=O)OC)cc1[N+](=O)[O-]
Solvent: O
Product: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 91 %

Procedure:
A 3-L round-bottomed flask under N2 equipped with an overhead stirrer, a condenser and a thermocouple is charged with 2-amino-4-ethoxy-5-nitrobenzoic acid methyl ester (80 g, 333 mmol) and N,N-dimethylformamide dimethyl acetal (500 mL). The reaction mixture is heated to reflux (100° C.). Once the thick slurry becomes homogeneous and the reaction is complete, the reaction mixture is cooled to 25 to 30° C. The reaction mixture is diluted with water (3 L) and the resulting suspension is filtered. The filter cake is washed with water (3×500 mL) and dried under vacuum (50 mm Hg) at 55° C. to provide the title compound as an off-white solid (89.6 g, 91% yield, >90% purity by NMR integration). 1H NMR (300 MHz, DMSO-d6): 8.23 (s, 1H), 7.81 (s, 1H), 6.71 (s, 1H), 4.22 (q, J=7 Hz), 3.68 (s, 3H), 3.09 (s, 3H), 2.97 (s, 3H), 1.40 (t, J=7 Hz, 3H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCC(=O)c1cccs1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1cccs1)c1ccc(Cl)cc1
Yield: 99.5 %

Procedure:
5.0 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride, 10.0 g of sodium bicarbonate and 4.78 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 7.6 g of N-(4-chlorobenzoyl)-N-[(2-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]=2[Cl:13])[NH:6][CH:5]=1)#[N:2]>N.[Ni]>[NH2:2][CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]=2[Cl:13])[NH:6][CH:5]=1
Reactant: N#CCc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Agent: [Ni]
Agent: N
Product: NCCc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Yield: 103.6 %

Procedure:
A solution of 3-cyanomethyl-4-chloro-5-benzyloxyindole (1.00 g, 3.37 mmol) in methanolic ammonia (30 ml) was hydrogenated over Raney nickel for 21/2 hours at room temperature, at 30 p.s.i. pressure. After filtering off the catalyst, the filtrate was evaporated to give 3-(2-aminoethyl)-4-chloro-5-benzyloxyindole as an oil (1.05 g, 100%). Part of this product (170 mg, 0.57 mmol) was treated with excess ethereal HCl, and the mixture was evaporated to dryness to leave a pink solid, which was recrystallised from ethanol/ether to give 3-(2-amino-ethyl)-4-chloro-5-benzyloxyindole hydrochloride (108 mg) m.p. 224°-5° C.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[OH:10][CH2:9][C@H:7]([NH:8][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a suspension of (R)-(−)-2-phenylglycinol (15.34 g, 111.82 mmol) and rhodanine (14.65 g, 110 mmol) in acetonitrile (200 mL) was added DIPEA (20.03 mL, 115 mmol) at room temperature. Then, it gave a clear solution within 2 min and this solution was cooled to 0° C. To this, mercuric chloride (31.22 g, 115 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (1.0 L). The combined solvents were removed under the vacuum and the crude residue was diluted with water (250 mL) and ethyl acetate (250 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The two organic extracts were washed separately with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude yellow solid. This solid was dissolved in acetonitrile (˜100 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with cold acetonitrile. After drying in air, 12.99 g (50% yield) of 2-(2-hydroxy-1-(R)-phenyl-ethylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C11H12N2O2S (M-H2O) 218.0514, found 218.0511.