Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[C:13]=1[C:12](=[O:14])[NH:11][C:10](=[O:15])[NH:9]2)([O:3][CH3:4])=[O:2].NC1C([C:28](OC)=[O:29])=C(C(OC)=O)NC=1C1C=CC=CC=1.[N-]=C=O.[Na+]>>[C:12]([C:13]1[C:8]([NH:9][C:10]([NH2:11])=[O:15])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6][C:5]=1[C:1]([O:3][CH3:4])=[O:2])([O:29][CH3:28])=[O:14]
Reactant: COC(=O)c1[nH]c(-c2ccccc2)c(N)c1C(=O)OC
Reactant: COC(=O)c1[nH]c(-c2ccccc2)c2[nH]c(=O)[nH]c(=O)c12
Agent: [N-]=C=O
Agent: [Na+]
Product: COC(=O)c1[nH]c(-c2ccccc2)c(NC(N)=O)c1C(=O)OC

Procedure:
5-Carbomethoxy-7-phenyl-6H-pyrrolo[3,4-d]pyrimidine-2,4(1H,3H)-dione, from 3-amino-4,5-dicarbomethoxy-2-phenyl-pyrrole and sodium isocyanate. The intermediate 4,5-dicarbomethoxy-2-phenyl-3-ureido-pyrrole is isolated. M.p. 246°-8° C (from methanol/water). Yield of the title compound 88.5%. M.p. 320°-7° C. (from methanol/water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][N:9]([CH3:13])[CH2:10]2)=[CH:5][CH:4]=1.OC1C=C2C(C(C3C=CC=CC=3)[CH2:26][N:27]([CH3:31])[CH2:28]2)=CC=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O>[CH3:26][N:27]([CH2:31][CH2:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][N:9]([CH3:13])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:28]
Reactant: CN1Cc2cc(O)ccc2C(c2ccccc2)C1
Reactant: COc1ccc2c(c1)CN(C)CC2c1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Product: CN(C)CCOc1ccc2c(c1)CN(C)CC2c1ccccc1

Procedure:
The title compound was prepared from (+)- 7 -methoxy- 2 -methyl- 4 -phenyl- 1,2,3,4 -terahydro isoquinoline via (+)- 7 -hydroxy- 2 -methyl- 4 -phenyl- 1,2,3,4 -tetrahydro isoquinoline which was characterised as its hydrochloride salt m.p. 222°-3° C. (methanol-ether) [α]D25 + 24.1° (water) by the method of Example 1. The title compound was characterised as its dihydrochloride salt m.p. 160°-4° (hydroscopic) (ethanol ethyl acetate), [α]D5 + 13° (water). -tetrahydro
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12][C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12][C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1
Reactant: O=C1CCc2cc(F)cc(F)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC1CCc2cc(F)cc(F)c2CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
1,3-Difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (1.5 g, 7.6 mmol) was dissolved in 30 mL of dry THF, the solution was cooled to 0° C. under argon and 1M LAH (7.5 mL, 7.5 mmol) in THF was added over 2 minutes. The mixture was stirred at 0° C. for 1 hour and then 0.28 mL of water, 0.28 mL of 15% aqueous sodium hydroxide and 0.9 mL of water were added sequentially. The mixture was stirred for 5 minutes, filtered, washed with ethyl acetate and dried over magnesium sulfate. Evaporation of the solvents gave 1,3-difluoro-6,7,8,9-tetrahydro-7-hydroxy-5H-benzocycloheptene (1.55 g, 7.8 mmol) as an oil.
Reaction SMILES: C1(C)C=CC(S(N[C@H](C(O)=O)C)(=O)=[O:8])=CC=1.ON1C2C=CC=CC=2N=N1.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.COC1C=C(O)C=C(OC)C=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:36]1([NH:35][C:34]([NH:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1cc(O)cc(OC)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
For reaction by the active ester process, 14.6 g. (0.06 mol) N-(toluene-4-sulphonyl)-L-alanine and 12.2 g. (0.09 mol) N-hydroxybenzotriazole are dissolved in 300 ml. anhydrous ethyl acetate, cooled to 0° C. and mixed with 12.4 g. (0.06 mol) dicyclohexylcarbodiimide. For the formation of the active ester, the reaction mixture is stirred for 2 hours at 0° C. and then for a further 2 hours at ambient temperature. After the addition of 6.2 g. (0.04 mol) 3,5-dimethoxyphenol and 5.5 ml. (0.04 mol) triethylamine, the reaction mixture is stirred for 15 hours at ambient temperature. The N,N'-dicyclohexylurea formed is filtered off with suction and the filtrate is evaporated in a vacuum at a maximum bath temperature of 50° C. The residue is taken up in 200 ml. ethyl acetate and successively washed, in each case three times, with 100 ml. amounts of 5% citric acid and then with 100 ml. amounts of 5% sodium bicarbonate solution. After drying with anhydrous sodium sulphate, the organic phase is evaporated in a vacuum. The oily crude product obtained is purified column chromatographically with a silica gel column, using toluene-ethyl acetate (4:1 v/v) as elution agent. After evaporating the appropriately collected fractions, the residue is dissolved in a little methylene chloride and the product precipitated out by the addition of diethyl ether, there being obtained 5.8 g. (38% of theory) 1-[N-(toluene-4'-sulphonyl)-L-alanyloxy]-3,5-dimethoxybenzene in the form of colorless crystals; m.p. 110° C.; αD20 : -52.5° (c=1% in acetone).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)O1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:42]2[CH:43]=[C:44]([CH:51]=[CH:52][C:53]=2[F:54])[C:45]([NH:47][CH:48]([CH3:50])[CH3:49])=[O:46])=[N:39][C:40]=1Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:42]2[CH:43]=[C:44]([CH:51]=[CH:52][C:53]=2[F:54])[C:45]([NH:47][CH:48]([CH3:50])[CH3:49])=[O:46])=[N:39][C:40]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][N:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[N:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]1
Reactant: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(B4OC(C)(C)C(C)(C)O4)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(-c3cc4c(N5CCC[C@H](N)C5)ccnc4cn3)n2)c1
Yield: 21 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 3-(5-amino-6-chloropyridin-2-yl)-4-fluoro-N-isopropylbenzamide ((1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.2 equiv.) in 3:1 DME/2M Na2CO3 was heated at 120° C. for 20 hours. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-3-(5-amino-6-(4-(3-aminopiperidin-1-yl)-1,7-naphthyridin-6-yl)pyridin-2-yl)-4-fluoro-N-isopropylbenzamide (21%). LC/MS=500.3 (M+H), LC=2.36 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2.O>C(O)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:21])([CH3:22])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:17])[F:18])[CH:14]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture that consists of 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (320 mg, 1 mmol) and 5-amino-2-methylquinoline (190 mg, 1.2 mmol) in acetic acid (2 ml) is stirred for 16 hours at room temperature, diluted with 10 ml of toluene and heated for 4 hours in a water separator. The batch is concentrated by evaporation, whereby the acetic acid is removed azeotropically with toluene. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 274 mg of the product accumulates as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][N:71]1[CH2:76][CH2:75][CH:74]([NH2:77])[CH2:73][CH2:72]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([C:25](=[O:26])[NH:77][CH:74]4[CH2:75][CH2:76][N:71]([CH3:70])[CH2:72][CH2:73]4)[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NC2CCN(C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 mL) was added 1-methyl-piperidin-4-ylamine (21 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:35])=[O:34])[CH2:21][CH2:20]3)=[N:6][C:5]=2[CH:7]=1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Reactant: Clc1ccc2oc(Cl)nc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OC1CCN(c2nc3cc(Cl)ccc3o2)CC1)c1ccccn1

Procedure:
Compound 24 is prepared using synthesis method 3 using intermediates 2h and 6a (yield: 92%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-:12].[Na+]>>[N+:8]([C:6]1[CH:7]=[C:2]([OH:12])[C:3]([OH:11])=[CH:4][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)c(O)c1
Temperature: 60 °C
Yield: 84 %

Procedure:
2-chloro-4-nitro-phenol (64.44 g, 0.4 mole) and 300 ml 4M NaOH solution were refluxed with heating for 6 hours. After cooling down and filtration with vacuuming, the filtrate (crystal) was dissolved in a little warm water (60° C.). The solution was adjusted to pH 2.0 with 10% HCl and cooled down while stirring. After filtration, the filtrate was recrystallized with water to yield 4-nitro-1,2-benzenediol (52.1 g, yield rate 84%).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:3][CH:4]([OH:6])[CH3:5]>[Pd].CCCCCC>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5]
Reactant: CC(C)=CCCC(C)=CC(C)O
Agent: [Pd]
Solvent: CCCCCC
Product: CC(C)CCCC(C)CC(C)O
Temperature: 80 °C
Yield: 94.6 %

Procedure:
A mixture of 671.2 g of citral and 185.6 g of diethyl ether is added to an addition funnel. The citral mixture is then added dropwise over a five hour period to a nitrogen blanketed, stirred, 5 L, 3-neck, round bottom flask equipped with a reflux condenser containing 1.6 L of 3.0 M methylmagnesium bromide solution and an additional 740 ml of diethyl ether. The reaction flask is situated in an ice water bath to control exotherm and subsequent ether reflux. After addition is complete, the ice water bath is removed and the reaction allowed to mix for an additional 2 hours at 20-25° C. at which point the reaction mixture is added to 3.5 Kg of cracked ice with good mixing. To this mixture is added 1570 g of 30% sulfuric acid solution. The aqueous acid layer is drained and the remaining ether layer washed twice with 2 L of water. The ether layer is concentrated by evaporation of the ether under vacuum to yield 720.6 g of 4,8-dimethyl-3,7-nonadien-2-ol. To a glass autoclave liner is added 249.8 g of the 4,8-dimethyl-3,7-nonadien-2-ol, 5.8 g of 5% palladium on activated carbon and 200 ml of n-hexane. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged twice with 250 psig N2, once with 250 psig H2 and then charged with 100 psig H2. Upon mixing, the reaction initiates and begins consuming H2 and exotherms to 75° C. The autoclave is heated to 80° C., boosted to 500 psig with H2, mixed for 3 hours and then cooled to 30° C. The reaction mixture is removed from autoclave, filtered to remove catalyst and concentrated by evaporation of n-hexane under vacuum to yield 242 g of 4,8-dimethyl-2-nonanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[S:8](=[O:10])(=[O:9])[NH:7][C:6]2=[O:16].F[B-](F)(F)F.[CH2:22]([O+](CC)CC)[CH3:23]>ClCCl>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[S:8](=[O:9])(=[O:10])[N:7]=[C:6]([O:16][CH2:22][CH3:23])[C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC2=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NS(=O)(=O)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5,6-dimethoxysaccharin (0.8 g) in dichloromethane (100 ml) was added triethyloxonium tetrafluoroborate (3.5 ml, 1M soln in CH2Cl2) and the solution stirred at room temperature for 3 hrs. After extraction with aqueous sodium bicarbonate, the organic phase was dried and concentrated. Purification by column chromatography (silica, chloroform) gave the title compound (0.2 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]2(O)C3C[CH:11]4[CH2:12][CH:13](C[CH:9]2[CH2:10]4)C3)C=CC=[CH:3][CH:2]=1.C(O)CCCCCCCCC>>[CH3:3][CH2:2][CH2:1][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OC1(Cc2ccccc2)C2CC3CC(C2)CC1C3
Solvent: CCCCCCCCCCO
Product: CCCCCCCCCC

Procedure:
1-Chlorosulfonyl-3-phenyl-spiro[azetidin-2-one-4,2'-tricyclo[3.3.1.13,7 ]decane] (Compound A) was prepared by first synthesizing 2-(phenylmethyl)-tricyclo[3.3.1.13,7 ]decan-2-ol and dehydrating this decanol compound to form 2-(phenylmethylene)-tricyclo[3.3.1.3,7 ]decane in accordance with the following procedure:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](I)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:18]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(I)c(OCc2ccccc2)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Yield: 83 %

Procedure:
12 g (28 mmol) of methyl 4-benzyloxy-3-tert-butyl-5-iodobenzoate are dissolved with 5.8 g (42 mmol) of 4-methylbenzeneboronic acid and 12.7 g (84 mmol) of caesium fluoride in 400 mL of dioxane. The reaction medium is degassed with a flow of nitrogen for 15 minutes, and 1.7 g (1.4 mmol) of tetrakis(triphenylphosphine)palladium are then added. The reaction medium is refluxed for 4 hours and then cooled and hydrolysed. After extraction with ethyl acetate, the organic phase is filtered and concentrated. The residue is purified by chromatography (eluent: 98 heptane/2 ethyl acetate): a colorless oil is obtained (m=9 g, yield=83%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:5]=1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reactant: OB(O)c1ccccc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Yield: 44.5 %

Procedure:
A solution of ethyl 4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate (30 mg, 0.07 mmol) and phenyl boronic acid (14 mg, 0.11 mmol) in toluene (3 mL) was degassed with argon for 15 minutes. To this solution was added Pd(PPh3)4 (9 mg, 0.007 mmol), Na2CO3 (23 mg, 0.22 mmol) and the reaction was heated to reflux for 3 days. The reaction was diluted with EtOAc (20 mL) and extracted with saturated NH4Cl solution (2×20 mL), brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give ethyl 4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidine-5-carboxylate (14 mg, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9](O)=[O:10])=[C:4]([F:27])[CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:41][O:42][NH2:43].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:23][CH2:24]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH:43][O:42][CH3:41])=[O:10])=[C:4]([F:27])[CH:3]=1
Reactant: O=C(O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CONC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 45 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.453 mmol) in dichloromethane (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.680 mmol) and 4-(dimethylamino)pyridine (2.266 mmol) at room temperature. This mixture was stirred for 10 min at which point O-methylhydroxylamine hydrochloride (0.906 mmol) was added. The reaction vessel was sealed and the mixture was stirred at room temperature for 18 h and at 45° C. for 24 h. The reaction was then cooled to room temperature and was treated with pyridine (0.5 mL). The reaction vessel was resealed and stirred overnight in an oil bath at 45° C. At this point the reaction was cooled to room temperature and treated with additional portions of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.680 mmol) and O-methylhydroxylamine hydrochloride (0.906 mmol). The reaction vessel was resealed and stirred in an oil bath at 45° C. for 2 h. The reaction mixture was then concentrated to dryness in vacuo. The resulting orange residue was dissolved in dichloromethane (10 mL) and was concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-40% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a clear oily solid (89 mg, 38% yield). MS(ES)+ m/e 470.1/472.1 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9]([NH2:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[C:1]1([N:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[CH:10][C:9]([NH2:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)C(C(F)(F)F)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: Nc1cc(C(F)(F)F)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
A mixture of 1-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-amine (1.47 g, 6.41 mmol) and DDQ (1.748 g, 7.7 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 4 hours. The crude product was purified by silica gel chromatography twice (with 15-35% and 10-30% EtOAc/hexane as eluants) to afford 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-amine as an oil (0.666 g, 46%). 1H NMR (300 MHz, CDCl3) δ 7.42 (m, 5H), 6.18 (s, 1H), 3.82 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([CH:10]=O)[CH2:9][CH2:8]1.[S].C(O)(=O)C.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])[CH2:26]2)=[N:22][C:23]=1[NH2:24]>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1([C:10]2[NH:24][C:23]3=[N:22][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:26]4)=[CH:20][CH:19]=[C:18]3[N:17]=2)[CH2:8][CH2:9]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=CC1(c2ncccn2)CC1
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5ncccn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 80 °C

Procedure:
1-(Pyrimidin-2-yl)cyclopropanecarbaldehyde (0.11 g, 0.747 mmol), sulfur (40 mg, 1.24 mmol), and acetic acid (0.6 mL) were added to a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared during the previous step, in ethanol. The reaction mixture was heated to 80° C. for 18 h. The solvent was removed under reduced pressure and the crude material was purified via preparative HPLC to afford the title compound (8 mg). MS (ES+APCI) (M+H) 418.2; LCMS retention time 3.273 min (Method S1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[Cl:11].[NH4+].[Cl-]>CO.[Zn]>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Br)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 1-bromo-2-chloro-3-nitrobenzene (3.0 g, 12.7 mmol) in MeOH (127 ml) was added Zn dust (8.30 g, 127 mmol) followed by NH4Cl (6.79 g, 127 mmol) which resulted in a significant exotherm. The heterogeneous reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite and concentrated to an off-white solid. To this solid was added EtOAc and the resulting mixture was sonicated for 10 minutes. The mixture was filtered through Celite and washed with EtOAc. The combine filtrates were concentrated in vacuo to afford 2.17 g (10.5 mmol, 79%) of 3-bromo-2-chloroaniline: LCMS(m/z): 205.9 (MH+); tR=0.87 minute: 1H NMR (400 MHz, CDCl3) δ 6.62-6.66 (m, 1H) 6.87 (t, J=8.0 Hz, 1H) 6.97 (d, J=7.8 Hz, 1H) 7.22 (d, J=9.0 Hz, 1H).