Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:16][CH:17]=2)=[O:23])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 71 %

Procedure:
As described for example 75b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (76 mg, 71%) which was obtained as a white solid. MS: m/e=414.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:16]CCO1.[Li]CCCC.[CH2:28]([O:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#N)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC1C=CC(S([O-])(=O)=[O:52])=CC=1.C1C=C[NH+]=CC=1>C1COCC1.CC(C)=O.O>[CH2:28]([O:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[CH2:10][CH2:11][C:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[O:52])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(Br)c(CCC2(c3ccccc3)OCCO2)c1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li]CCCC
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2ccc(OCc3ccccc3)cc2)c(CCC(=O)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 236.8 %

Procedure:
A solution of 2-[2-(2-Bromo-5-methoxy-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane (0.9 g, 2.5 mmol) in 10 ml of dry THF was cooled to −78° C. and n-BuLi (2.5 M in hexane, 1 ml) was added dropwise. The solution was stirred at −78° C. for 2 h and 4-benzyloxy-benzonitrile (0.575 g, 2.75 mmol) in 2 ml of THF was added. The mixture was allowed to warm to room temperature and refluxed overnight. The solution was then quenched with sat. NH4Cl and the solvent was evaporated. A solution of the residue in 20 ml of wet acetone, 5 ml of H2O containing PPTS (188 mg, 0.75 mmol) was refluxed overnight. Regular workup and column purification afforded an unoptimized weight of 0.8 g 3-[2-(4-Benzyloxy-benzoyl)-5-methoxy-phenyl]-1-phenyl-propan-1-one.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 110 °C
Yield: 12.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.2 g, 0.54 mmol, prepared according to Example 5 in WO 01/70741) and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.6 g, 2.16 mmol) were combined in toluene (3 mL) and heated to 110° C. overnight. The reaction was quenched by the addition of succinic anhydride (0.2 g) and allowed to cool giving a solid. This solid was suspended in CH2Cl2 and filtered to give a white solid. The filtrate was washed with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel chromatography eluting with 75% ethyl acetate:25% hexanes to provide 4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-carboxylic acid tert-butyl ester (0.04 g, 13%). MS (APCI) M++1: Calc'd, 584.19. Found, 584.1.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=2)[C:18]=1[C:29](Cl)=[O:30]>C(Cl)Cl.[N+](C)([O-])=O>[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[C:29]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1)=[O:30]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
To a solution of 2.1 g (10 mmol) of 2-trichloroacetyl-1H-pyrrole (commercially available) in CH2Cl2 (35 mL) and nitromethane (17.5 mL), 1.66 g (12.5 mmol) of AlCl3 was added in one portion. Then 2.96 g (12.5 mmol) of 5-methyl-3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid chloride (example 2, step 1) in 5 mL of CH2Cl2 was added dropwise. The reaction mixture was stirred at room temperature for 18 h before poured onto ice-water. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The combined organic solution was dried over Na2SO4, and evaporated to dryness. The obtained solid was washed extensively with petroleum ether to give 2.93 g 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-2-trichloroacetyl-1H-pyrrole in 70% yield as yellow solid. (m/e): 414.8 (M+; 100%).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]([C:14]3[C:15]([O:21][CH3:22])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=[C:35]([N:48]([CH3:50])[CH3:49])[N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:38]4[C:33]([O:32][CH3:31])=[N:34][C:35]([N:48]([CH3:49])[CH3:50])=[N:36][CH:37]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C:15]([O:21][CH3:22])=[N:16][CH:17]=1
Reactant: COc1ncc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(C#N)cc1
Reactant: COc1nc(N(C)C)ncc1B1OC(C)(C)C(C)(C)O1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N(C)C)ncc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cc(Cl)cnc1OC)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-2-methoxy-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate BG) and 4-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate W) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. ESI-MS: tR=1.20 min, [M+H]+ 558/560 (LC-MS 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[CH2:28][CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:33]([O:32][CH2:31][CH2:30][N:27]([C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:28][CH3:29])[CH3:34]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Reactant: CCOCCN(CC)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g), 4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl borate (0.46 g), 1M potassium carbonate solution (3.2 ml), ethanol (3.2 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g) as green amorphous.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH2:13])([CH3:4])[CH3:3].C(O)(=O)C.[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO>[C:2]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCCC1N
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCCC1NC1CCCC1
Temperature: 50 °C
Yield: 58.2 %

Procedure:
To a solution of [(1RS,2SR)-2-aminocyclopentyl-carbamic acid 1,1-dimethylethyl ester (CAS 365996-19-6) (500 mg, 2.497 mmol) in 10 ml methanol was added acetic acid (0.714 ml, 12.49 mmol) and cyclopentanone (0.665 ml, 7.491 mmol). The mixture was heated in a 50° C. oil bath for 1.5 hour. The solution was cooled to room temperature and sodium cyanoborohydride (370 mg, 5.0 mmol) was added portionwise. The mixture was heated in a 50° C. oil bath for 2.5 hours. The solution was cooled in an ice bath and quenched by dropwise addition of 6 ml 2N NaOH. The methanol was removed in vacuo. The aqueous layer was diluted with water and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified on silica gel (eluent: heptane/ethyl acetate 0 to 100%) to provide 0.39 g (58%) of the title compound as a light brown solid. MS (m/e): 269.3 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CC[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])C.[Cl:15]CCl>>[Cl:15][CH2:14][C:12]1[N:8]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]=[CH:11][CH:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: ClCCl
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)n1cccc1CCl
Reaction time: 0.5 h

Procedure:
At 0° C. methanesulfonyl chloride (136 μl) was added dropwise to a solution of the product of example 51b (205 mg) and DIPEA (307 μl) in dichloromethane (6 ml). After stirring for 30 min, the reaction mixture was diluted with dichloromethane (30 ml) and washed with ice water (30 ml), 10% HCl (30 ml) and sat. NaHCO3. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Yield: 252 mg.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH2:19]1[CH2:23]OC[CH2:20]1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[C:20]#[C:19][CH3:23])=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: C1CCOC1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Reaction time: 0.25 h

Procedure:
An oven-dried 3L 3-neck flask equipped with a mechanical stirrer, nitrogen inlet and nitrogen outlet was placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a separate oven-dried and nitrogen-flushed 500 mL round bottom flask, compound 1.1 (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with gentle warming. The solution of 1.1 was added over 15 minutes. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes and quenched with aqueous NH4Cl (0.6 N, 750 mL) and diluted with hexanes (800 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH ˜2 with saturated aqueous KHSO4 and extracted with EtOAc (2×400 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (37 g). 1H NMR (500 MHz, acetone-d6) δ 8.26 (s, 1H); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (br s, 1H); 4.46 (d, 1H, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s, 3H). MS ESI (pos.) m/e: 599.0 (2M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:6]([CH3:23])=[C:5]2[C:24]([OH:26])=[O:25].[C:27](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=1)[C:6]([CH3:23])=[C:5]2[C:24]([O:26][CH3:27])=[O:25]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (9.0 g, 24.64 mmol) in dichloromethane (120 mL) at 0° C. was added 5 drops of DMF. Oxalyl chloride (3.24 mL, 37.0 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h. The mixture was warmed to room temperature, and an additional portion of oxalyl chloride (3.24 mL, 37.0 mmol) was added. The reaction mixture was stirred overnight. Methanol (50 mL) was added and the mixture was stirred overnight. The solvent was removed under reduced pressure to afford methyl 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification in the next step. MS (m/z) 380.1 (M+H+).
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([N:10]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)[CH2:14]2.[H-].[K+].C1(CBr)CC1>CCOC(C)=O>[CH:1]1([CH2:5][O:6][C:7]23[CH2:8][CH:9]4[CH2:15][CH:13]([CH2:12][CH:11]([N:10]4[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]2)[CH2:14]3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(O)(C3)C2
Reactant: C1CCOC1
Agent: BrCC1CC1
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(OCC1CC1)(C3)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A 15 mL seal tube fitted with magnetic stirrer was charged with 5 mL of THF, tert-butyl 5-hydroxy-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-6 (50 mg, 0.2 mmol). To the tube, potassium hydride (20 mg, 0.5 mmol) was added at 0° C., under N2 atm. The reaction mass was stirred at room temperature for 30 minutes. To this mixture, cyclopropyl methyl bromide (40 mg, 0.3 mmol) was slowly added at 0° C. and the resulting reaction mass was refluxed at 60° C. under sealed condition for 12 hrs. After completion of the reaction (reaction was monitored by TLC), reaction mixture was quenched with cold water and extracted with ethyl acetate (25 ml×3). The organic layer was washed with sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give crude Intermediate-17, which was subjected to column chromatogram (18% EtOAc in PE) to obtain an oily mass (50 mg, yield=80%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH2:28][CH3:29])=[C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][NH:37][C:36]=3[N:35]=2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].C1(C)C=CC=CC=1>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH2:28][CH3:29])=[C:26]([NH:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][NH:37][C:36]=3[N:35]=2)[N:25]=[CH:24][N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(NCCCc2ccc3c(n2)NCCC3)ncnc1NCC(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1c(NCCCc2ccc3c(n2)NCCC3)ncnc1NCC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
65 mg (0.11 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-[5-ethyl-6-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propylamino]-pyrimidin-4-ylamino]-propionate in 5 ml of dichloromethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature for 16 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 45 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: C([O:4][C:5]1[C:12]([Br:13])=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][C:6]=1[Br:14])(=O)C.O.NN.O.Cl>C1COCC1.CO>[Br:13][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([Br:14])[C:5]=1[OH:4])[CH:9]=[CH2:10]
Reactant: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(Br)c(O)c(Br)c1

Procedure:
10 g of 4-acetoxy-3,5-dibromostyrene are dissolved in 50 ml THF and 25 ml methanol, 12 g hydrazine hydrate (80% aqueous solution) is added, and the cloudy mixture is then converted into a clear solution by adding 3 ml of water. After 40 minutes it is acidified with a semi-concentrated HCl to pH 2 and extracted twice with ether, the ether phase is washed twice with water and dried over sodium sulfate, and the ether is removed with a rotary evaporator at room temperature under aspirator vacuum. 8.5 g of crude product remain, from which 6.45 g of white crystals (mp 74° C.) are obtained by recrystallization from petroleum ether.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[CH:18]C=C3[C:12]=2[CH2:13][O:14]C3=O)=[CH:7][CH:6]=1)[CH3:3].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C[O-].[Na+].CO.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38][CH3:39]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]2[C:13](=[O:14])[C:12]3[C:38]([C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:39][CH:18]=[CH:19][C:11]=3[NH:10][CH:9]2[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[CH:22][CH:21]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(Cl)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (588 mg, 2 mmol) and 4-chlorobenzaldehyde (281 mg, 2 mmol) in anhydrous ethyl propionate (25 mL) was cooled to 0° C. The sodium methoxide in methanol solution (sodium (115 mg, 5 mmol) in anhydrous ethanol (10 mL)) was added dropwise and the mixture was stirred at 25° C. for 3 hr. The resulting mixture was quenched with water (5 mL), and then evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 mL×3) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product, which was purified by column chromatography (silica gel, dichloromethane to dichloromethane/methanol=30:1) to give the title compound (260 mg, yield 28%) as a yellow solid. LC-MS (ESI) m/z: 463 (M+1)+.
Reaction SMILES: [C:1]([NH:6][C:7](=[S:15])[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3]CC)=O.CC[O-].[K+].Cl[CH2:21][C:22]#[N:23]>CO>[CH:9]1([O:8][C:7]2[S:15][C:21]([C:22]#[N:23])=[C:1]([OH:3])[N:6]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)NC(=S)OC1CCCCC1
Reactant: N#CCCl
Agent: CC[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1sc(OC2CCCCC2)nc1O
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A suspension of 38.3 g of cyclohexyl N-carbethoxy-thiocarbamate and 11.56 g of potassium ethylate in 400 ml of methanol was stirred for 2 hours and 12.45 g of chloroacetonitrile were added thereto. The mixture was stirred for 48 hours at room temperature and was then concentrated to dryness. The residue was added to water and the aqueous phase was acidified with hydrochloric acid. The aqueous phase was extracted with ether and the ether phase was dried and concentrated to dryness to obtain 15 g of 2-cyclohexyloxy-4-hydroxy-5-cyanothiazole in the form of white crystals melting at 138° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:34][CH:35]3[CH2:40][CH2:39][CH:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH2:37][CH2:36]3)[N:24]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(S(C)(=O)=O)n2)C1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(NS(C)(=O)=O)CC3)n2)C1
Yield: 73.3 %

Procedure:
4-[3-(t-Butyl-dimethylsilyloxy)pyrrolidin-1-yl]-1-(2-methylsulfonyl-pyrimidin-4-yl)-1H-indole (about 160 mg, 0.35 mmol), N-(4-amino-cyclohexyl)-methanesulfonamide hydro-chloride (743 mg, 3.255 mmol) and DIEA (0.169 mL, 4.32 mmol) were mixed in NMP (7 mL) under Ar at 130° C. for 2.5 h. The reaction mixture was washed with NH4Cl/H2O and extracted into EtOAc (6×15 mL), and further washed with H2O (6×30 mL). The solvent was removed in vacuo to yield N-[4-(4-{4-[3-(t-butyl-dimethylsilanyloxy)-pyrrolidin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (150 mg).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>CC(C)=O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:22]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)=[O:9]
Reactant: BrC1C=CCCC1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccccc1OC1C=CCCC1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
In a 10-liter reactor there were introduced 633.4 g (5.19 moles) of salicylaldehyde, 5 liters of acetone and 717.3 g of potassium carbonate, and the mixture was left with stirring at room temperature. After precipitation of the phenate, 836 g (5.19 moles) of 3-bromocyclohexene were rapidly added dropwise, and the mixture was brought to reflux for 21/2 hours. After removal of the inorganic salts by filtration, and evaporation of the solvent, the residue was taken up in ethyl ether, washed with 10% caustic soda and then water, and the ether phase was then dried over Na2SO4. After filtration and elimination of the ether, there were obtained 975 g of 3-(2-formylphenoxy)cyclohexene, which was used directly in the following stage.