Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[C:10]2[Br:33])[CH2:8]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To 11 g (25.67 mmol) trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester (see Example 4) in 275 ml dry N,N-dimethylformamide, 5.18 g (28.24 mmol) N-bromosuccinimide are added in small portions. The solution is stirred at RT in the dark and under Argon for 17 h. Thereafter the solvent is evaporated, and the residue purified by chromatography on silicagel (solvent: hexane-ethyl acetate 3:1). Further purification is done by crystallization from acetonitrile. Analytical HPLC: tR=3.61 min (shorty); ES-MS: m/eo=506.9 and 508.9; mp: 124-125° C.; NMR (DMSO-d6): 8.18/s (1H), 7.25-7.5/several m's (6H), 7.09/“d” (1H); 7.04/s (1H); 6.98/“d” (1H); 5.38/m (1H); 5.13/s (2H); 3.69/s (3H); 3.50/m (2H); 3.29/m (1H); 2.62/m (2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:32])[CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:46])(C)C.CCOCC>CC(CC)=O>[ClH:46].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:32])[CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(C(c1ccccc1)c1ccccc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-diphenylacetyl-1,4,8-triazaspiro[4,5]decan-2-one (450 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (3.6 mL), water (8 μL), TMSCl (118 μL), and ether (10 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-diphenylacetyl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 402 mg (84%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:7][CH:8]=1)#[N:2].[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[NH2:12][CH2:11][CH2:10][NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C#N)cn1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NCCN)nc1
Reaction time: 0.5 h

Procedure:
7.9 g (30 mmol) of tert-butyl {2-[(5-cyanopyridin-2-yl)amino]ethyl}carbamate (Example 1A) were dissolved in 100 ml of 4N hydrogen chloride in dioxane and the mixture was stirred for 30 min. The reaction mixture was concentrated to half of its original volume and the same amount of diethyl ether was added. The reaction mixture was stirred for 20 min and the product was filtered off and washed with diethyl ether. This gave 7 g (94% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>CCO>[F:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([I:10])[CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1c(I)ccnc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1c(I)ccnc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-4-iodonicotinaldehyde (3.50 g, 13.94 mmol) in absolute EtOH (56 mL) was added sodium borohydride (0.264 g, 6.97 mmol) at room temperature. The reaction was stirred at room temperature for 1 h, followed by the slow addition of 1 M aqueous hydrochloric acid. The product was extracted with CH2Cl2 (repeated four times), and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The aqueous phase was basified to pH 8-10 with 2 M aqueous sodium hydroxide and extracted with diethylether (repeated four times). Then the organic layers were combined, dried over sodium sulfate, filtered, combined with the previously obtained residue and concentrated to dryness under vacuum. The residue was used without any purification in the next step. LC/MS m/z 254 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1Cl)([O-:14])=[O:13]>S1(CCCC1)(=O)=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CSc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 65 °C
Yield: 97.4 %

Procedure:
To a solution of 15.4 g (0.110 mole) of 4-(methylthio)phenol dissolved in 150 ml of sulfolane was added 4.40 g (0.110 mole) of NaOH. The mixture was heated to 65° C. and 20.25 g (0.100 mole) of 2,4-dinitrochlorobenzene added and the reaction mixture heated at 65° C. for 3.25 hrs. The product was recovered (29.8 g, 97.4% yield) as described in Example 1 and recrystallized from ethanol, which gave purified 1-(4-(methylthio)phenoxy)-2,4-dinitrobenzene, mp 119°-120.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C)C=O>[C:26]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[C:12]([NH2:18])[CH:13]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2N)cc1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a stirred solution of N-(4-methoxyphenyl)-2,4-diaminobenzamide (19 g, 73.8 mmol) in N,N-dimethylformamide (250 mL) was added pyridine (6.6 mL, 81 mmol), followed by acetic anhydride (6.6 mL, 70 mmol). After stirring overnight, the solvents were removed in vacuo and the residue was chromatographed over a silica gel (10% tetrahydrofuran/90% chloroform). The appropriate fractions were combined and concentrated in vacuo to give 5.3 g (24%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([Cl:15])=[O:8])[C:5]([Cl:11])=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)cnc1Cl
Yield: 99.4 %

Procedure:
To a slurry of 5-bromo-2-chloronicotinic acid (2.063 g, 8.725 mmol) in methylene chloride (20 mL) was slowly added oxalyl chloride (1.11 g, 8.725 mmol) followed by the addition of dimethylformamide (5 drops). After 4 H the mixture was concentrated in vacuo to provide 2.21 g of 5-bromo-2-chloropyridine-3-carbonyl chloride as a light brown solid, which was used as is in the next reaction.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH3:22][N:21]1[C:14]2[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:13]=2)[CH2:19][C@H:20]1[CH3:23]
Reactant: N#Cc1cccc(CO)c1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@@H]1Cn2c(cc(OCc3cccc(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9](OCC)=[O:10])[CH2:5][CH2:4]1.CC(C[AlH]CC(C)C)C>ClCCl>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1CCC(OC)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COC1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Into a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 4-methoxycyclohexane-1-carboxylate (1.3 g, 6.98 mmol) in dichloromethane (30 mL). This was followed by the addition of DIBAL-H (1 M in hexanes) (9 mL, 9 mmol) dropwise at −78° C. The reaction mixture was stirred for 3 h at −78° C., then quenched with 10 mL of NH4Cl (sat.). The aqueous phase was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 1 g (crude) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][CH2:40][CH3:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH2:39][CH2:40][CH3:41])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCBr
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccc(OC)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1)S(=O)(=O)c1cccc(OC(F)F)c1

Procedure:
The compound was prepared by analogy to the methods described for Preparation Example 2 and Example 1 from 4-{5-[(3-difluoromethoxybenzenesulfonyl)-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was reacted with sodium hydride and 1-bromopropane to yield 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-propylamino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was deprotected to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[O:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>N1C=CC=CC=1>[Cl:23][C:9]1[O:10][C:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(Cl)s1
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(Cl)s1
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[4-(5-chloro-2-thienyl)-2-oxo-4-oxazolin-5-yl]butanoate (12.5 g), phosphorus oxychloride (24.5 g) and pyridine (3.16 g) was heated to 120-130° C. and stirred for 45 minutes. There action mixture was poured into ice-water (200 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-4-(5-chloro-2-thienyl)-5-oxazolebutanoate was obtained as a yellow oil (5.79 g, 48%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20]O)[CH3:18])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Oc1cccc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
In 50 mL of tetrahydrofuran, 200 mg (1.51 mmol) of 1H-indole-4-ol and 527 mg (3.00 mmol) of 2-hydroxyethyl-methylcarbamic acid tert-butyl ester were dissolved, and 1.51 mL (3.00 mmol) of a diethyl azodicarboxylate 40% toluene solution and 788 mg (3.00 mmol) of triphenylphosphine were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was concentrated, and then partitioned between ethyl acetate and a saturated ammonium chloride aqueous solution. The organic layer was washed with a saturated sodium chloride solution, dried and concentrated, and the obtained residue was purified by a silica gel column (50 g, n-hexane:ethyl acetate=2:1) to obtain 433 mg (99%) of [2-(1H-indol-4-yloxy)ethyl]-methyl-carbamic acid tert-butyl ester as a viscous oily substance.
Reaction SMILES: Cl.CO[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=O.[C:28]([O:31][CH2:32]C)(=[O:30])[CH3:29].C(O)C>>[CH3:32][O:31][C:28]([CH:29]1[CH2:4][CH2:6][CH2:7][N:8]1[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:26])[CH:11]=1)=[O:30]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: CNc1ccc(C(=O)N2CCCC2C(=O)OC)cc1N

Procedure:
The same procedure is used as in (2). Rf value: 0.41 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1.C(N(CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:19])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
4-Chlorobenzoyl chloride (19.5 g, 111 mmol) was added over 10 min. to a stirred, cooled (0° C.) solution of 4-chloro-2-methylaniline (15 g, 106 mmol) and triethylamine (22.2 mL, 16.1 g, 159 mmol) in dichloromethane (300 mL) and the mixture was stirred at room temperature for 2 h. Water (100 mL) was added and the dichloromethane was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 200 mL), water (200 mL) and ethyl acetate (1000 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with ether and the solid was collected and dried in vacuo to give the title compound (27.3 g, 92%). 1H NMR (360 MHz, CDCl3) δ 7.82 (3H, m), 7.79 (1H, br s), 7.48 (2H, d, J 8.5 Hz), 7.23 (2H, m), and 2.30 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:18]1[C:23]([CH3:24])=[C:22]([N:25]([CH:33]2[CH2:35][CH2:34]2)C(=O)OC(C)(C)C)[N:21]2[N:36]=[CH:37][C:38]([CH:39]=[O:40])=[C:20]2[N:19]=1.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.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH:1][C:18]1[C:23]([CH3:24])=[C:22]([NH:25][CH:33]2[CH2:34][CH2:35]2)[N:21]2[N:36]=[CH:37][C:38]([CH:39]=[O:40])=[C:20]2[N:19]=1)[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: Cc1c(Cl)nc2c(C=O)cnn2c1N(C(=O)OC(C)(C)C)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(Nc2ccc(C#N)cc2Cl)nc2c(C=O)cnn2c1NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To 4-amino-3-chlorobenzonitrile (52 mg, 0.34 mmol), Cs2CO3 (130 mg, 0.4 mmol) were added to tert-butyl 5-chloro-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (100 mg, 0.29 mmol) dissolved in 1,4-dioxane (1.1 mL). Racemic BINAP (11 mg, 0.017 mmol) and palladium(II) acetate (8 mg, 0.011 mmol) were then added. The mixture was sealed and irradiated at 110° C. for 60 min in the microwave. Et2O (3 mL) was added and the solution was filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). After stirring at room temperature for 1 hour, the solution was concentrated under a stream of air. The crude material was purified by silica gel chromatography (3% acetone/dichloromethane) to yield the product, 3-chloro-4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (34 mg, 33% yield). LCMS (M+1=367)
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:4](=[O:14])[CH:3]=1.CCN(C(C)C)C(C)C.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C(Cl)Cl>[O:14]=[C:4]1[CH:3]=[C:2]([O:1][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)=CC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (680 mg, 3.41 mmol) in DCM (12 mL) was added DIEA (1.192 mL, 6.83 mmol) and tosyl chloride (651 mg, 3.41 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0 to 50% EtOAc/heptane). Pure fractions were combined, evaporated and dried to give desired product as a white solid (0.98 g, 81%). LCMS (m/z): 354.1 (MH+), 0.97 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=8.22 Hz, 2H) 7.54 (d, J=7.83 Hz, 2H) 5.77 (s, 1H) 4.33 (s, 2H) 2.43 (s, 3H) 1.41 (s, 9H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:34])([F:36])[F:35])=[CH:17][N:16]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2-(2-(2-(2-((4-(piperazin-1-ylmethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (25) (11 mg, 0.022 mmol) was dissolved in methanol (1 mL). 37% Formaldehyde solution (7 μL) was added followed by sodium triacetoxyborohydride (24 mg, 0.11 mmol). The mixture was stirred vigorously at room temperature for two hours then concentrated. The residue was suspended in 10% sodium hydroxide (1 mL) and brine (2 mL) then extracted with ethyl acetate (5×2 mL). The combined ethyl acetate phases were washed with brine, dried over sodium sulfate, evaporated and the residue evaporated from DCM to give the title compound (36) (10.3 mg, 94% yield) as an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.46 (d, J=0.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.18-7.13 (m, 1H), 7.13-7.07 (m, 3H), 3.57 (s, 2H), 3.46 (s, 2H), 3.06 (qd, J=6.8, 3.1 Hz, 2H), 3.01-2.94 (m, 2H), 2.54 (s, 8H), 2.29 (s, 3H). LCMS Method C, 4.70 min; m/z 513.2 [M+H]+; m/z 511.0 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:11]([Si:18]1(C2C=CC=CC=2)[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:11]([Si@H:18]1[CH2:19][CH2:20][C@H:21]([C:24]([O:10][C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)=[O:25])[CH2:22][CH2:23]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2cc(F)c(F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4,5-trifluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[N:45]1>CC(=O)CC>[N:44]1([CH2:43][CH2:42][CH2:41][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[N:45]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: ClCCCn1ncc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4ncc5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.14 g, 0.33 mmol), potassium carbonate (0.068 g, 0.5 mmol) and sodium iodide (0.015 g, 0.01 mmol) in 2-butanone (3 mL), was added 1-(3-chloropropyl)-1H-indazole (0.065 g, 0.33 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.16 g, 84%); 1H NMR (DMSO-d6): δ 1.51 (s, 9H), 1.59 (d, 2H, J=12.8 Hz), 2.03 (t, 2H, J=6.4 Hz), 2.24 (t, 2H, J=7.2 Hz), 2.57-2.67 (m, 4H), 3.56 (t, 2H, J=6.4 Hz), 4.47-4.63 (m, 6H), 6.78 (t, 1H, J=7.2 Hz), 6.85-6.87 (m, 2H), 7.11 (t, 1H, J=8 Hz), 7.24 (t, 2H, J=8 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.48-7.51 (m, 2H), 7.70-7.83 (m, 4H), 8.07 (s, 1H); MS for C35H41N5O3 m/z 580.14 (M+H)+.