Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Br[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20].C(=O)([O-])[O-].[K+].[K+].[OH-].[OH:32][CH2:33][CH2:34][N+:35]([CH3:38])([CH3:37])[CH3:36]>O>[OH:32][CH2:33][CH2:34][N+:35]([CH3:38])([CH3:37])[CH3:36].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:18]([CH3:24])([CH3:23])[C:19]([O-:21])=[O:20])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 100 g (0.43 mol) of (4-chlorophenyl)(4-hydroxyphenyl)-methanone and 148 g (0.82 mol) of methyl 2-bromo-2-methylpropanoate is prepared in a 1 l reactor maintained under a nitrogen atmosphere. The mixture is heated to 145° C., with thorough stirring, and 69 g (0.5 mol) of potassium carbonate are added. The reaction medium is maintained at 145° C. for 3 hours, with thorough stirring, during which time the water formed by the reaction is collected in the distillate. The pressure in the reactor is then gradually reduced in order to remove the excess brominated reactant by distillation. The mixture is then cooled to about 100° C. and 300 ml of n-propanol are added. The resulting mixture is stirred for 10 mm at 90° C. and then filtered at this temperature to remove the insoluble mineral salts. The residual solid is rinsed with 100 ml of hot n-propanol, which is combined with the previous filtrates. The solution obtained is placed in the 1 l reactor under a nitrogen atmosphere and 121.5 g (0.45 mol) of a 45% aqueous solution of choline hydroxide are added. The reaction mixture is stirred for 3 hours under gentle reflux of the solvent and about 240 ml of solvent are then distilled, 130 ml of n-propanol being added to the reactor. The reactor contents are subsequently filtered on a clarifying filter and then cooled slowly to about 15° C. The resulting suspension is filtered on an aspirator and the isolated solid is rinsed with 100 ml of cold n-propanol and then dried in a vacuum oven.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1

Procedure:
A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AD) (0.300 g, 0.00068 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.304 g, 0.00102 mol), sodium carbonate (0.180 g, 0.00170 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.155 g, 0.00032 mol): 1H NMR (DMSO-d6, 400 MHz) 8.78 (s, 2H), 8.25 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.65 (m, 1H), 1.44-2.36 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.33.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]3([CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:28])[CH2:15]1)=[O:13])[CH2:8]2.[BH4-].[Na+]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]3([CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]3[OH:28])[CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCCC2(Cc3ccccc3C2=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCCC2(Cc3ccccc3C2O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To a solution of N-(2-adamantyl)-1-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide (3.0 mg, 0.079 mmol) in MeOH (3 mL) was added NaBH4 (12 mg, 0.317 mmol) at 0° C. under nitrogen. The reaction mixture was stirred for 4 h under N2 at rt. The reaction mixture was evaporated to give a residue, which was purified by preparative HPLC to afford N-(2-adamantyl)-1-hydroxy-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide (12 mg, 40%). 1HNMR (CD3OD, 400 MHZ): δ=1.51-1.75 (m, 5H), 1.78˜1.81 (m, 4H), 1.82˜2.00 (m, 11H), 2.50 (m, 1H), 3.00 (d, 1H), 3.20 (m, 1H), 3.55 (m, 1H), 3.65 (m, 1H), 3.81 (s, 1H), 4.75 (s, 1H), 7.22 (m, 3H), 7.388 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]12[C:19](=[O:20])[O:18][C:16](=[O:17])[CH:14]1[CH2:15]2.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:19]([C@H:13]2[CH2:15][C@H:14]2[C:16]([OH:18])=[O:17])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(=O)C2CC12
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1ccccc1-c1ccccc1)[C@H]1C[C@H]1C(=O)O
Reaction time: 48 h
Yield: 31.4 %

Procedure:
12.7 g (82.4 millimoles) of biphenyl, followed by 10.0 g (89.2 millimoles) of 1,2-cyclopropanedicarboxylic acid anhydride, are added, in each case a little at a time, to 29.7 g (0.22 mole) of anhydrous aluminum chloride in 100 ml of carbon disulfide whilst stirring at room temperature. The mixture is refluxed for 4 hours and then left to stand for 2 days at ambient temperature. After decanting the carbon disulfide, the reaction mixture is introduced into 200 g of ice and 50 ml of concentrated hydrochloric acid. The solid which precipitates is filtered off, washed with water and recrystallized from propanol. 6.9 g (31% of theory) of cis-2-(p-biphenylcarbonyl)-cyclopropanecarboxylic acid are obtained as colorless crystals, of melting point 222°-223° C. after a further recrystallization, from ethanol.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[F:17][CH:18]([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][CH:18]([F:17])[O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)F)cc3)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (Description 13) (100 mg, 0.456 mmol) in DMF (10 ml) was added 4-[(difluoromethyl)oxy]benzenesulfonyl chloride (133 mg, 0.547 mmol). Finally DIPEA (0.239 ml, 1.368 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (72 mg) as a white powder.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH:31]1[O:35][C:34](=[O:36])[NH:33][CH2:32]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH:31]4[O:35][C:34](=[O:36])[NH:33][CH2:32]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCC(CCl)O1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1NCC(CN2CN(c3ccccc3)C3(CCN(C4CCCCCCCCC4)CC3)C2=O)O1

Procedure:
The title compound, white solid, m. p. 174° C. and MS: m/e=469.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 5-chloromethyl-2-oxazolidinone.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23].N([O-])=O.[Na+].C(O)(=O)C.[ClH:32]>O.Cl[Cu]>[Cl:32][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23]
Reactant: Nc1ccc(NC(=O)C(F)(F)c2ccccc2)c(F)c1CCO
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccccc1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A suspension of N-[4-amino-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide (1.63 g, 5.00 mmol), as prepared according to the procedure of the preceding step, in 6N HCl (9 mL) was cooled in an ice-bath, and then a solution of NaNO2 (434 mg, 6.30 mmol) in H2O (2.4 mL) was added over a period of 5 minutes. After 30 minutes, acetic acid (2.9 mL) and concentrated HCl (2.9 mL) were added and the reaction mixture stirred for 1 hour. To this mixture was added a solution of CuCl (848 mg, 8.55 mmol) in concentrated HCl (5 mL) over a period of 20 minutes. After stirring in an ice-bath for 3 hours, the reaction mixture was extracted with EtOAc (200 mL×3). The extracts were combined, washed with H2O (2 times) and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to deliver the title compound (0.845 g, 48% yield) as a pale orange oil. 1H-NMR (400 MHz, CDCl3)δ 8.31 (s, 1H), 8.14 (t, J=8.6 Hz, 1H), 7.68-7.66 (m, 2H), 7.54-7.46 (m, 3H), 7.19 (dd, J=8.9, 1.7 Hz, 1H), 3.86 (dd, J=12.6, 6.5 Hz., 2H), 3.09 (dt, J=6.7, 2.3 Hz, 2H), 1.58 (t, J=5.7 Hz, 1H). Mass spectrum (LCMS, ESI) calc'd for C16H14ClF3NO2 (M+H): 344.1. Found: 344.2.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]1([CH2:14][CH2:13][CH2:12]1)[C:6]2=[N:15]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:14][CH2:13][CH2:12]3)[C:6]2=[NH:15])=[CH:10][CH:11]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C1c2cc(Br)ccc2CC12CCC2
Reaction time: 3 h

Procedure:
Hydrochloric acid (4M in 1,4-dioxane, 14.89 mL, 59.55 mmol) was added to a solution of N-(5′-bromospiro[cyclobutane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 54 Step 1, 2.11 g, 5.96 mmol) in anhydrous 1,4-dioxane (60 mL), and the resulting mixture was stirred under an argon atmosphere for 3 h. Et2O (4 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM (100 mL), and sat. aq. NaHCO3 (100 mL). The phases were separated and the organic layer concentrated to afford the title compound that was used as such without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:25](=[O:38])[NH:26][CH2:27][C:28]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)C)(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@H:9]([NH:7][CH3:6])[C:25]([NH:26][CH2:27][C:28]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][CH2:30][CH2:31]2)=[O:38])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-{2-(4-Benzyloxy-phenyl)-1-[(1-phenyl-cyclobutylmethyl)-carbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (from Step 1; 1.07 g, 2.02 mmol) in methylene chloride (10 mL) was added TFA (2.5 mL). The solution was stirred at room temperature for 2 hours and then concentrated in vacuo. Coevaporisation with methylene chloride was carried out twice to give the desired product which was used without further purification.
Reaction SMILES: [C:1]1([P:7](=S)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=[O:22].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]1([P:7](=[O:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of triphenylphosphine sulfide (0.3 g) and ethyl acetate (10 ml) is added thionyl chloride (0.16 ml) at room temperature, and the mixture is stirred for 2 hours at the same temperature. The reaction mixture is shaken with aqueous 6% sodium hydrogen carbonate (20 ml) and the resulting mass is stirred for another 2 hours. The organic layer which forms on standing for a while is taken, washed with water, filtered to remove a solid mass and concentrated to dryness. The residue is crystallized from ether to give triphenylphosphine oxide (0.26 g). m.p. 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=[N:13]O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: ON=Cc1ncc(C(F)(F)F)cc1Cl
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde oxime (1.0 eq.) and Burgess reagent (1.5 eq.) in tetrahydrofuran (0.5 M) was heated to 65° C. and stirred for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo to give a solid that was carried onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:23][N:22]=2)[CH2:12]1.ClC(Cl)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOCC>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:35])[CH2:19][S:20][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[CH:25][N:26]=2)[CH2:12]1
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCNC3)nc2)cc1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCN(Cc4cccc(Cl)c4Cl)C3)nc2)cc1
Reaction time: 8 h

Procedure:
2,3-Dichlorobenzaldehyde (115 mg, 0.66 mmol, 1.5 equiv.) was added to N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylthio]acetamide in dichloroethane (3.4 mL, 0.44 mmol). Excess Na(OAc)3BH (0.2 g, 0.9 mmol, ~3 equiv.) was added and the resulting suspension was stirred vigorously overnight. The reaction mixture was diluted with ether and quenched with 1 M hydrochloric acid to afford a cloudy mixture. The organic layer was carefully removed and the aqueous phase made basic with 5 M aqueous sodium hydroxide to pH 11. After thorough extraction with ethyl acetate, the combined organic phases was washed with brine, then dried over sodium sulfate and concentrated. Chromatography on silica (0-10% methanol in ethyl acetate) afforded N-(1-(2,3-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-ylsulfanyl]acetamide that was converted to the hydrochloride salt using 4 M hydrochloric acid solution in dioxane and ether (60 mg).
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[C:34](=[CH:35][C:36]([C:40]3[N:44]=[CH:43][N:42]([C:45]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:41]=3)=[CH:37][CH:38]=2)[C:33]([C:64]2[CH:65]=[C:66]([NH2:70])[CH:67]=[CH:68][CH:69]=2)=[N:32]1>ClCCl>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[C:34](=[CH:35][C:36]([C:40]3[N:44]=[CH:43][N:42]([C:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:41]=3)=[CH:37][CH:38]=2)[C:33]([C:64]2[CH:65]=[C:66]([NH:70][C:9](=[O:11])[CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:12])[CH:67]=[CH:68][CH:69]=2)=[N:32]1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenoxypropanoic acid (0.045 g, 0.274 mmol) in 2.5 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.057 g, 0.298 mmol). The reaction was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) dissolved in 1 mL of dichloromethane, was added to the solution. The reaction was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between water and dichloromethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 751 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[CH:10][N:9]2[CH3:17])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:14]([C:11]5[C:12](=[O:13])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]([CH3:17])[CH:10]=5)=[O:16])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Yield: 80.3 %

Procedure:
In the same manner as in Example 46 and using 2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (280 mg, 1.2 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.80 mmol), HATU (460 mg, 1.2 mmol), N,N-diisopropylethylamine (310 mg, 2.4 mmol) and N,N-dimethylformamide (6 mL) as starting materials, the title compound (350 mg, 81%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:30][C:29]#[CH:28])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To a solution of the product from step 2 (2.0 g, 6.82 mmol) in anhydrous DMF (50 mL) was added dry K2CO3 (4.6 g, 33 mmol) and allowed to stir for 15 min. Propargyl bromide (1.214 g, 10.20 mmol) in anhydrous DMF (10 mL) was added and the reaction mixture stirred at 50° C. for 6 h, then at rt for 48 h. The reaction mixture was concentrated, taken up in EtOAc, washed with water, dried over anhydrous MgSO4 and the solvent removed in vacuo. The product was purified by silica gel flash chromatography using EtOAc/hexane to obtain the title compound (2.0 g, 88%).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:22][CH3:23])=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[C:1]12([C:11]3[C:12]([O:22][CH3:23])=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=3)[C:16]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:25]=3[OH:24])=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1cc(OC)c(C23CC4CC(CC(C4)C2)C3)cc1C(=O)O
Reactant: NCc1ccc(O)cc1O
Product: COc1cc(OC)c(C23CC4CC(CC(C4)C2)C3)cc1C(=O)NCc1ccc(O)cc1O

Procedure:
0.03 g of the target compound is obtained as white solid in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2,4-dimethoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 2,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(C)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)cccc1CBr
Temperature: 25 °C

Procedure:
A solution of 1-chloro-2-methoxy-3-methyl-benzene (13.40 g, 85.60 mmol), NBS (15.30 g, 86.00 mmol) and a catalytic amount of benzoyl peroxide (150 mg) in CCl4 was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with pentane. The solvent was distilled off and the residue was purified by column chromatography using pentane as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 4.56 (s, 2H), 7.04 (t, J=7.62 Hz, 1H), 7.29 (dd, J=7.62 Hz, 1H), 7.34 (dd, J=7.92 Hz, 1H).