Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([O:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:7]2[N:8]([C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1.Cl>>[Cl:3][C:4]1[CH:5]=[C:6]([O:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:7]2[N:8]([C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(Cl)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc2c(OCc3ncccc3F)cc(Cl)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
28.1 ml (28.1 mmol) 1 M lithium hydroxide solution were added to 2.0 g (5.62 mmol) of ethyl 6-chloro-8-[(3-fluoropyridin-2-yl)methoxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate from Example 128A, and the mixture was stirred at 40° C. for 2.5 h. The reaction mixture, cooled to RT, was adjusted to about pH 4 using 6 N aqueous hydrochloric acid, the solvent was concentrated to half its original volume and the precipitated solid was filtered off with suction and dried under reduced pressure. This gave 1.97 g (102% of theory) of the target compound (a proportion possibly as hydrochloride salt).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].C(Cl)Cl.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.O>[Si:21]([O:5][CH2:4][CH2:3][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[NH2:1])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
A round-bottom flask was charged with (R)-3-amino-3-(3,4-dichlorophenyl)propan-1-ol (9.25 g, 42.0 mmol, CASRN 147611-61-8), DMAP (0.513 g, 4.20 mmol) and DCM (84.1 mL) then a solution of TBDMS-Cl (6.65 g, 44.1 mmol) and DCM (10 mL) was added. The reaction was stirred at RT for 2 d. The reaction mixture was poured into water and extracted with DCM. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:8 to 500:10) to afford 10.2 g (72%) of (R)-3-(tert-butyl dimethylsilyloxy)-1-(3,4-dichlorophenyl)propan-1-amine (186): m/z (APCI-pos) M+1=334.0.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1>>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:7]1
Reactant: CC1CNCCN1
Reactant: N#Cc1ccc(Cl)nc1
Product: CC1CN(c2ccc(C#N)cn2)CCN1
Yield: 45 %

Procedure:
This compound was synthesized from 2-methyl-piperazine and 6-chloronicotinonitrile as described for example 39 step 1 (90 mg, yield 45%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=2.0 Hz, 1H), 7.79 (dd, J=9.2 Hz, J=2.4 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 4.24 (t, J=10.2 Hz, 2H), 2.94-2.87 (m, 1H), 2.86-2.77 (m, 1H), 2.63-2.55 (m, 2H), 2.45-2.41 (m, 1H), 0.99 (d, J=6.1 Hz, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
Using a procedure similar to Example 1B except starting with 4-methoxycarbonyl-1,2-benzenediamine and 4-t-butylbenzoyl chloride, the title compound was obtained as a solid (10.8 g, 65%); MS(FD): 326.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:12][CH3:13])[C:10]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][C:8](OC)([CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[CH2:20]([O:19][C:10]1[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:12][CH3:13])[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8](=[CH2:24])[CH:9]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOC1=CC(C)(OC)C=C(OCCCC)C1(OC)OCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1C=C(OCCCC)C(OC)(OCCCC)C(OCCCC)=C1
Yield: 87.8 %

Procedure:
The procedure of Example 9 was repeated by using 334 mg of 1,5,6-tributoxy-3,6-dimethoxy-3-methyl-1,4-cyclohexadiene, 10 ml of ether and 15 mg of aluminum chloride, recovering 290 mg of an oily crude product. The crude product was purified by silica gel column chromatography using a 20:1 benzene-ethyl acetate mixture, giving 268 mg of 1,5,6-tributoxy-6 -methoxy-3-methylidene-1,4-cyclohexadiene in 89% of the theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].C(Cl)Cl>ClCCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(OC1CN2CCC1CC2)n1ccnc1

Procedure:
According to Method C, 3-quinuclidol is first reacted with a carbonyldiimidazole (DCI) in an inert solvent (e.g. DCM, 1,2-DCE) at room temperature in order to obtain the corresponding imidazole-1-carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester. Then, arylalkylamine (II) is metalated in an inert solvent (e.g. THF) using BuLi and the ester was added at a temperature ranging from 0° C. to room temperature.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)[CH2:3]1.[CH3:32][C:33]1[S:37][C:36]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)=[N:35][CH:34]=1.CCN(CC)CC>C1COCC1>[CH3:32][C:33]1[S:37][C:36]([NH:38][C:39](=[O:40])[NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:16]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)[CH2:3]2)=[N:35][CH:34]=1
Reactant: NC(=O)c1cnc(N2CCC[C@@H](N)C2)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Cc1cnc(NC(=O)Oc2ccccc2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cnc(NC(=O)N[C@@H]2CCCN(c3cc(Nc4ccc(C(=O)N5CCOCC5)cc4)c(C(N)=O)cn3)C2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
A mixture of (R)-6-(3-aminopiperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (34 mg, 0.080 mmol) and phenyl 5-methylthiazol-2-ylcarbamate (24.39 mg, 0.104 mmol) in THF (2 mL) was added Et3N (0.015 mL, 0.104 mmol) and capped in a vial and stirred at rt overnight. The reaction mixture was chromatographed (ISCO Companion 40 g silica gel column and eluted with NH4OH/MeOH/CH2Cl2 gradient (4-10%) to give 20 mg of (R)-6-(3-(3-(5-methylthiazol-2-yl)ureido)piperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a white solid. LCMS: (M+H)+=565.19. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (1H, s), 8.36 (1H, br. s.), 7.40 (2H, d, J=8.35 Hz), 7.24 (2H, d, J=8.57 Hz), 6.83 (1H, s), 6.35 (1H, s), 3.31-4.02 (13H, m), 2.30 (3H, s), 1.94 (1H, br. s.), 1.53-1.80 (3H, m).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.Cl.CCCCCC>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:2]2[CH:1]=[CH:5][CH:4]=[CH:3]2)=[CH:23][CH:24]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reactant: C1=CCC=C1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1ccc(CC(Cc2ccc(Cl)cc2)=C2C=CC=C2)cc1
Temperature: -78 °C
Yield: 22.2 %

Procedure:
Under a nitrogen atmosphere, a 100-mL three-necked flask was charged with 0.66 g (9.22 mmol) of lithium cyclopentadiene and 10 mL of dehydrated THF, and the mixture was stirred. This solution was cooled (to −78° C.) in a dry ice/methanol bath, and 2.50 g (8.96 mmol) of bis(4-chlorobenzyl)ketone dissolved in 15 mL of dehydrated THF was added dropwise. Subsequently, the mixture was stirred for 17 hours while gradually warming to room temperature. Then, 1 N hydrochloric acid was added to the resulting brown-black solution to terminate the reaction. Thereafter, hexane was added to perform liquid-liquid phase separation, and the aqueous layer was subjected to extraction with hexane twice. The resultant was combined with the organic layer obtained previously. The resultant liquid was then washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain a target product as a yellow powder (yield 0.65 g (22%)). The target product was identified by 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)cc(OC)c1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To a solution of 3,5-Dimethoxy-benzaldehyde (9.5 g, 57.17 mmol) in pyridine (60 ml), malonic acid (9 g, 85.725 mmol) was added, and followed by piperidine (2 ml), the mixture was heated to 100° C. and stirred at this temperature for 6 hs under N2. Then most of pridine was removed, and the residue was poured into water (250 ml), acidified to PH=3 by aq.HCl, the precipitate was collected and dried to give product (10.9 g, 91.8%). LC-MS: m/e 207 (M−1)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[C:7]=1[CH3:13])(=[O:3])[CH3:2].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.N(OC(C)(C)C)=O>CCCCCCC>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc(N)c1C
Reactant: c1ccoc1
Agent: CC(C)(C)ON=O
Solvent: CCCCCCC
Product: CC(=O)OCc1cccc(-c2ccco2)c1C
Yield: 32.4 %

Procedure:
A stirred solution of 10.0 g (0.056 mol) of 3-amino-2-methylphenylmethyl acetate and 37.4 g (0.055 mol) of furan was heated to reflux, and 8.6 g (0.084 mol) of tert-butyl nitrite was added dropwise during 30 minutes. Upon complete addition, the reaction mixture was heated under reflux an additional 1.5 hours, then cooled, and 300 mL of heptane was added. The solution was filtered through 50 g of silica gel. The silica gel was washed with 400 mL of pentane. The wash and filtrate were combined and concentrated under reduced pressure to give a residual oil which was subjected to column chromatography on silica gel, eluting with toluene. The appropriate fractions were combined and concentrated under reduced pressure to give a residual oil. The oil was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 4.1 g of 3-(2-furanyl)-2-methylphenylmethyl acetate, b.p. 94±2° C./0.05 mm.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[CH:1]1([NH:5][C:20]([C:19]2[CH:23]=[CH:24][N:25]=[CH:26][C:18]=2[NH:17][C:15]([C:13]2[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=[C:9]([CH:6]3[CH2:8][CH2:7]3)[N:14]=2)=[O:16])=[O:21])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 35 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclobutylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (35%) as amorphous yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:15][CH2:16]I.[Li+].CC([N-]C(C)C)C.C(O)(=O)C>C1COCC1>[Cl:15][CH2:16][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCI
Reactant: COC(=O)c1cccc2c1OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(CCl)c1cccc2c1OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester (100 mg, 0.515 mmol) and chloroiodomethane (0.075 ml, 1.03 mmol) in 1 ml of THF was added a solution of LDA in THF (2M, 0.57 ml, 1.13 mmol) dropwise at −78° C. over 15 min. The reaction mixture was stirred at −78° C. for 10 min. A solution of acetic acid (0.75 ml) in THF (5 ml) was added dropwise over 5 min at −78° C. The resulting solution was stirred at the same temperature for additional 10 min. and was then partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo to give the crude 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone as a light brown liquid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][P:5]([O-:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].[H-].[Na+].CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>C1COCC1>[CH3:33][N:32]([CH3:34])[C:30](=[O:31])[CH2:29][P:5](=[O:12])([O:6][CH2:7][C:8]([F:11])([F:9])[F:10])[O:4][CH2:3][C:2]([F:1])([F:13])[F:14]
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Reactant: CN(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Temperature: 10 °C
Yield: 34 %

Procedure:
Bis(2,2,2 trifluoroethyl)phosphite (5.0 mmol, 0.79 mL) was added to a solution of sodium hydride (0.420 g, 0.018 mol) and HMPA (8.6 mmol, 1.5 mL) at 10° C. in THF (20 mL). Immediately after addition, 2-bromo-N,N-dimethylacetamide (3.9 mmol) was added dropwise. The reaction temperature was maintained at 10° C. for 4.5 hours. The reaction was then quenched with saturated aqueous ammonium chloride (2 mL) and standard aqueous work-up was performed. Final purification by flash column chromatography (silica gel, 80% hexane, 20% ethyl acetate) yielded the desired compound (34%) as a colorless oil. c). To a solution of potassium tert-butoxide (705 mg, 6.33 mmol) in anhydrous THF (25 mL) at 0° C., bis(2,2,2-trifluoroethyl)phosphite (1.00 mL, 6.33 mmol) was added. 2-bromo-N,N-dimethylacetamide (12.66 mmol) was then added by syringe. Upon completion of the addition step, the reaction was allowed to proceed for one hour with monitoring by TLC. The reaction was then quenched with a saturated solution of aqueous ammonium chloride (20 mL). The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic extracts were washed with water (3×20 mL) and with a saturated sodium chloride solution (1×20 mL). The solvent was removed by rotary evaporation and the crude material was further concentrated under oil pump vacuum. The final product was purified by column chromatography (silica gel, 2:1 hexanes/ethyl acetate) yielding the desired compound (41%). (ii) From bis-(2,2,2-trifluoroethyl)phosphonoacetic acid.
Reaction SMILES: [C:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][C:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:2]
Reactant: COC(=O)C1(C(C)=O)CCCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(Cl)C1(C(=O)OC)CCCCC1

Procedure:
23.5 g of methyl 1-acetyl-1-cyclohexyl-carboxylate dissolved in 100 cm3 of dry methylene chloride were heated under reflux for 6 hours in the presence of 30 g of phosphorus pentachloride. The mixture was then poured on to ice. The methylene chloride solution was separated off and washed with water and then with bicarbonate. After drying over magnesium sulphate, the solution was concentrated and methyl 1-(1'-chlorovinyl)-1-cyclohexyl-carboxylate was then distilled; this product was in the form of a colourless liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[NH2:12])=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:12][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cc1noc([C@H](N)Cc2c[nH]c3ccccc23)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1noc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-2-(1H-Indol-3-yl)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (400 mg, 1.65 mmol) and 4-dimethylamino-4-phenylcyclohexanone (358.7 g, 1.65 mmol) in anhydrous tetrahydrofuran (50 mL) was mixed with sodium sulphate (1.1 g) and stirred for 2 h at room temperature. After adding acetic acid (248 mg, 4.1 mmol) sodium triacetoxyboron hydride (524 mg, 2.47 mmol) was added and the reaction mixture stirred for 16 h at room temperature. The solvent was removed in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was purified by flash chromatography (400 g, 20×5.6 cm) with ethyl acetate/isopropanol/triethylamine (10:0.3:0.01→5:1:0.1).
Reaction SMILES: Cl.[CH:2]1([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([N:21]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[N:18][CH:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CO>[CH:2]1([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH2:21])=[N:18][CH:17]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: c1ccc(C(=Nc2ncc(-c3ccccc3COC3CCCCC3)s2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2ccccc2COC2CCCCC2)s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
75 ml of an aqueous hydrochloric acid solution (1 M) are added to 11 g of 5-{-2-[(cyclohexyloxy)methyl]phenyl}-N-(diphenylmethylene)-1,3-thiazol-2-amine, obtained in step 1.4, in solution in 150 ml of methanol, and the mixture is stirred for 18 hours at 20° C. The mixture is evaporated to dryness, the residue is taken up in diethyl ether and washed with an aqueous sodium hydroxide solution (0.5 M). The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a silica gel column, eluting with a dichloromethane/methanol 98/2 (v/v) mixture, to give 5.3 g of a beige-colored solid. m.p.=102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:22]([NH2:24])=[O:23])=[C:8]1[C:18]([NH:20][CH3:21])=[O:19].[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1>>[F:16][C:15]1[CH:14]=[C:13]2[C:4]([C:5]3[N:9]([CH:10]4[CH2:17][CH:12]2[CH2:11]4)[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:7]([C:22]([NH2:24])=[O:23])[N:6]=3)=[CH:3][C:2]=1[C:34]#[C:33][C@@:31]([OH:35])([C:28]1[CH:27]=[C:26]([CH3:25])[O:30][N:29]=1)[CH3:32]
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
9-Bromo-10-fluoro-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide (125 mg) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 19.5 mg of 10-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide following reverse phase hplc purification. MS (Q1) 464 (M)+. 1H NMR (400 MHz, DMSO) δ 10.59 (q, J=4.6 Hz, 1H), 8.85 (d, J=7.5 Hz, 1H), 8.28 (s, 1H), 7.74 (s, 1H), 7.32 (d, J=10.1 Hz, 1H), 6.58 (s, 1H), 6.36 (s, 1H), 6.19-6.03 (m, 1H), 3.73-3.61 (m, 1H), 3.18-3.05 (m, 2H), 2.78 (d, J=4.5 Hz, 3H), 2.41 (s, 4H), 1.68 (d, J=12.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1cnc(N)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)ncc2C)cn1
Temperature: 120 °C
Yield: 42.5 %

Procedure:
To 4-chloro-5-methylpyrimidin-2-amine (250 mg, 1.74 mmol), tetrakistriphenylphosphine palladium (0) (100 mg, 0.087 mmol) and 6-methoxypyridin-3-ylboronic acid (398 mg, 2.60 mmol), 1,2-DME (6 mL) and Na2CO3 (1.74 mL, 2 M, 3.47 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using acetonitrile and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-amine (160 mg, 43%). ESI-MS m/z calc. 216.10, found 217.5 (M+1)+. Retention time 0.52 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1ccc(Br)cc1N
Temperature: 70 °C

Procedure:
A suspension of 4-bromo-N-methyl-2-nitroaniline (5328 mg, 22.04 mmol) in EtOH (100 ml) was treated with SnCl2.2H2O (25.61 g, 110.2 mmol) and the resulting mixture heated at 70° C. under an atmosphere of Nitrogen for 5 h. The reaction mixture was then cooled to rt and treated with ice-water (50 ml) followed by aqueous NaOH (4 N) until pH>8. This basic mixture was then extracted with EtOAc (3×150 ml) and the combined extracts washed with brine (3×100 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=2.68 (s, 3 H), 4.74 (brs, 3 H), 6.27 (d, 1 H, J=8.4 Hz), 6.61 (dd, 1 H, J=2.0 & 8.4 Hz) and 6.66 (d, 1 H, J=2.0 Hz). MS (ES+): m/z 201.10 and 203.12 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15](I)=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([C:21]#[N:22])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(C#N)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (490 mg, 1.26 mmol) was added 356 mg (3 mmol) of Zn(CN)2, 140 mg of Pd(PPh3)4 and 4 mL of DMF. The mixture was stirred at 90° C. for 3 h. After cooling to room temperature the reaction mixture was loaded onto a silica gel column and was purified by column chromatography to give 260 mg (72% yield) of desired 5-cyano-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was obtained as a white solid.