Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>O1CCCC1>[C:16]([Si:13]([CH3:15])([CH3:14])[O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 98 %

Procedure:
4-nitrophenethylalcohol (1.0 g, 5.98 mmol) was dissolved in tetrahydrofuran (20 ml), sequentially added with t-butyldimethylsilyl chloride (990 mg, 6.58 mmol) and imidazole (450 mg, 6.58 mmol). The resulting mixture was stirred for one day and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (ethylacetate:hexane=1:8) to obtain the title compound (1.65 g, yield: 98%, yellow oil).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=O)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[CH3:1][CH:2]1[CH2:8][C:7](=[S:23])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1
Reactant: CC1CC(=O)Nc2ccccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1CC(=S)Nc2ccccc2N1
Temperature: 80 °C
Yield: 123.4 %

Procedure:
A disposable tube was charged with 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (220 mg, 1.248 mmol) in THF (12 mL). Lawesson's Reagent (278 mg, 0.687 mmol) was added, and the solution was stirred at 80° C. 1 h. The solution was concentrated with celite and purified by silica gel chromatography to yield 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a yellow foam (0.163 g, 0.848 mmol, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:29])[NH:12][C:13]1[C:14]([CH3:28])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26]O)=[CH:20][CH:19]=1)[CH3:9].[NH:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]1>>[CH2:38]([O:37][C:35]([C:33]1[CH:34]=[N:30][N:31]([CH2:26][C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:28])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:29])=[CH:19][CH:20]=2)[CH:32]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1noc(-c2ccc(C#CCO)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Product: CCOC(=O)c1cnn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: {5-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-3-methyl-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and ethyl 4-pyrazolecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19]2[C:28]3[C:23](=[C:24]([C:29]([O:31]C)=O)[CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:33]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19]2[C:28]3[C:23](=[C:24]([C:29]([NH2:33])=[O:31])[CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc([N+](=O)[O-])c3)ncnc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc([N+](=O)[O-])c3)ncnc12
Reaction time: 48 h
Yield: 81.4 %

Procedure:
A suspension of methyl 4-{[1-(3-nitrophenyl)-3-pyrrolidin-1-ylpropyl]-amino}quinazoline-8-carboxylate (1 654.83 mg; 3.80 mmol; 1.00 eq.) and ammonia (16.29 ml; 7.00 M; 114.00 mmol; 30.00 eq.) in MeOH was stirred for 2 days. After concentration, the (1.3 g) of 4-{[1-(3-nitrophenyl)-3-pyrrolidin-1-ylpropyl]-amino}quinazoline-8-carboxamide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][C:13]([CH3:19])([CH3:18])[CH2:12]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)[C:15](=[O:17])[CH2:14][C:13]([CH3:19])([CH3:18])[CH2:12]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CC(C)(C)CC(=O)N1
Product: COc1cccc(OC)c1C1CC(C)(C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)-4,4-dimethylpiperidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.14 min.; [M+H]+: 437.96 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([O:19]C)=O)=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:23][C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)=[O:19])=[C:10]([OH:21])[C:9]=3[S:22][C:4]=2[CH:3]=1
Reactant: Nc1cnccn1
Reactant: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2cnccn2)=C(O)c2sc3cc(Cl)ccc3c2S1(=O)=O
Yield: 70 %

Procedure:
Prepared analogous to Example 1 from methyl 7-chloro-4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and amino-pyrazine with a yield of 70% of theory.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][C:10]([OH:13])=[N:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(C)C=CC=CC=1.[CH2:21]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[CH2:21]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:13][C:10]2[N:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][N:9]=2)=[O:33])=[CH:30][CH:29]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCc1cnc(O)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(C(=O)Oc2ncc(CCCCCC)cn2)cc1
Yield: 57.2 %

Procedure:
This 5-hexylpyrimidin-2-ol (1.8 g, 10 mmol) was dissolved in pyridine (2 ml), followed by adding dropwise to the solution, a toluene solution (30 ml) of p-hexyloxybenzoyl chloride (2.4 g, 10 mmol), stirring at 50° C. for 4 hours, further adding toluene (50 ml) to the reaction mixture to carry out extraction, washing the toluene layer twice with 6N-HCl aqueous solution (30 ml), further washing 5 times with 2N-NaOH aqueous solution (40 ml), washing with pure water until the aqueous layer became pH 7, drying the toluene layer over anhydrous Na2SO4 and distilling off toluene to obtain raw crystals (3.1 g) (yield 81%), which were then purified by activated alumina chromatography (solvent: toluene) and recrystallized from ethanol to obtain 5-hexylpyrimidin-2-yl p-hexyloxybenzoate (2.2 g) (yield 58%). This compound exhibited liquid crystallinity and as to their phase transition points, C-N point was 28.4° C. and N-I point was 35° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([NH2:43])=[O:42])=[C:39]([F:46])[CH:38]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:41]([C:40]1[CH:44]=[CH:45][C:37]([NH:36][C:11](=[O:13])[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:38][C:39]=1[F:46])(=[O:42])[NH2:43]
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reactant: NC(=O)c1ccc(N)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc(C(N)=O)c(F)c2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid in pyridine was added EDC, DMAP, and 4-amino-2-fluorobenzamide (E336), and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propylcarbamate (E337).
Reaction SMILES: C(OC([N:8]([S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[C:9](=[NH:19])[NH:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=O)(C)(C)C.Cl.O1CCOC[CH2:34]1.O=S(Cl)Cl.CO>O1CCOCC1>[NH2:15][C@H:14]([C:16]([O:18][CH3:34])=[O:17])[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[NH:19])[NH:8][S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21]
Reactant: Cc1cc(C)c(S(=O)(=O)N(C(=N)NCCC[C@H](N)C(=O)O)C(=O)OC(C)(C)C)c(C)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.10 g of Nω -t-butoxycarbonyl-Nω -mesitylenesulfonyl-L-arginine [Boc-Arg(Mts)-OH] was dissolved in 31 ml of dry dioxane and 31 ml of 4N HCl-dioxane was added thereto. The obtained mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to dryness and then crystallized by adding dry ether. The target product was collected by centrifugation, washed with dry ether several times and dried in a desiccator. Thus 1.1 g of HCl.H-Arg(Mts)-OH from which Boc groups had been removed was obtained. This product was next added to a solution, which had been prepared by slowly adding 2.9 ml of SOCl2 to 10.6 ml of methanol and stirring at -10° C. for 10 minutes, and the obtained mixture was stirred for 15 hours, concentrated to dryness, crystallized from dry ether, centrifuged, washed with dry ether several times and dried. Thus 0.94 g of HCl.H-Arg(Mts)-OMe was obtained.
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:2]2[O:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(S)cc1
Reactant: O=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Sc2ccc(C=O)o2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 91.5 %

Procedure:
To a solution of 2-bromo-5-furaldehyde (20.0 g, 114.29 mmol) in acetone (200 mL) was added 4-methoxybenzenethiol (15.5 mL, 125.75 mmol) and potassium carbonate (20 g). The reaction mixture was stirred at room temperature for 19 hours, and then filtered and concentrated on a rotary evaporator. The solid obtained was recrystallized from hexanes (300 mL) and ethyl acetate (50 mL) to give yellowish crystals (24.50 g).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:21][C:14]1[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC(C)Oc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 76.6 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-isopropoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.035 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred overnight at 20 C. The product mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4 and concentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.24 (s, 1 H), 6.64 (s, 1 H), 4.48 (m, 1 H), 2.98 (m, 3 H), 2.87 (m, 3 H), 1.36 (m, 6 H), 1.30 (d, J=7 Hz, 3 H). MS calculated for C14H20BrNO+H: 298, observed: 298.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:22][C:18]1[C:19]([F:21])=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc(Br)c(F)cc1Br
Reactant: COc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2cc(F)c(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 2 L RB flask was charged with 2-fluoro-4-methoxyphenol (49.6 g, 349 mmol), 2,5-dibromo-4-fluorobenzoic acid (80 g, 269 mmol), ethyl acetate (1.316 mL, 13.43 mmol), cesium carbonate (192 g, 591 mmol) and toluene (1200 mL). To the mixture at was added copper(I) triflate toluene complex (2:1) (1.713 g, 8.06 mmol) and it was stirred at room temperature for 20 minutes. The solution was then heated to 75° C. for 16 hours at which point the toluene was removed under reduced pressure. The solution was dissolved in 1.5 liters of water and washed with 250 ml of EtOAc. The aqeuous layer was acidified to pH 1 with concentrated HCl and the resulting precipitant was collected by filtration and washed with water. The derived solid was washed with a 1:1 solution of ethyl acetate and hexane, then dried under vacuum to afford 5-bromo-4-fluoro-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a light brown solid. MS m/z=358.8 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([OH:18])[CH:6]=1)=[O:4]>CO.ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([OH:18])[C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1=C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 14 h

Procedure:
[(1,2-Bis(2R,5R)-2,5-dimethylphospholano)benzene](cyclooctadiene)rhodium(I) tetrafluoroborate (23 mg, 1 mol %) was added to a degassed solution of (3S,4R)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid methyl ester (1 g, 3.9 mmol) in methanol (5 ml). The reaction mixture was transferred to a bomb and, after purging with nitrogen and then hydrogen, a hydrogen pressure of 5 bar was applied and the reaction stirred for 14 h. The pressure was released and the bomb purged with nitrogen. Concentration of the reaction mixture gave a residue which was redissolved in dichloromethane (5 ml) Addition of silica (0.5 g) was stirring removed the catalyst from the reaction, and filtration and concentration of the organic solution gave the title compound as an off-white solid of 98% d.e. in quantitative yield.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:24][C@H:23]([NH:25][C:26](=[O:41])[CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][NH:21]1)=[O:19])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:24][C@H:23]([NH:25][C:26](=[O:41])[CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][N:21]1[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:19])[CH3:16]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CC(c2ccccc2)c2ccccc2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)CC(c2ccccc2)c2ccccc2)CN1C(c1ccccc1)c1ccccc1
Yield: 57.2 %

Procedure:
To a solution of bromodiphenylmethane (0.4 g, 1.64 mmol) in butanone (10 ml) was added (2S,4S)-4-(3,3-diphenyl-propionylamino)-pyrrolidine-2-carboxylic acid ethyl ester (36) (0.6 g, 1.64 mmol), K2CO3 (0.23 g, 1.64 mmol) and KI (0.27 g, 1.64 mmol). The mixture was heated under reflux for 18 hours, and then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (1:1) gives 0.5 g the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+]>CO>[N:15]1[CH:16]=[C:12]([CH2:10][NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][CH:14]=1
Reactant: COc1cccc(N)c1
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(NCc2cnc[nH]2)c1
Yield: 81.2 %

Procedure:
To a solution of m-anisidine (0.91 ml, 8.12 mmol) in methanol (25 ml) was added 4-formylimidazole (0.86 g, 8.93 mmol). After stirring the mixture overnight at room temperature sodium borohydride (0.46 g, 12.2 mmol) was added. The reaction mixture was then concentrated in vacuo. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: methanol/dichloromethane 9:1) to yield a white solid (1.34 g, 18%); MS (ISP): 204.1 ([M+H]+).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 72.1 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 140 mg, 0.81 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 406 mg, 0.74 mmol) and DIPEA (0.514 mL, 2.94 mmol) in DMA (3 mL). The mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then part-purified by ion exchange chromatography, using an SCX column (20 g) and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined nad concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (245 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.17 (1H, dd), 3.76 (2H, dd), 3.97 (3H, s), 4.03-4.10 (2H, m), 6.29 (1H, s), 7.08 (1H, t), 7.14-7.21 (1H, m), 7.27 (1H, d), 7.45 (1H, d), 8.01 (1H, s), 8.28-8.37 (3H, m), 8.64 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 460.32.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])=[O:10])=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[O:12])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 110 °C
Reaction time: 70 h

Procedure:
4,4′-Dimethoxybenzil (5.0 g) was dissolved in acetic acid (95 mL). To the solution, 48 mass % aqueous HBr (31.2 g) was added dropwise at 70° C. over 10 minutes. After addition of HBr, the mixture was stirred at 110° C. for 70 hours. Subsequently, water (150 g) was added to the mixture, to thereby crystallize the product. The crude crystals were recovered through filtration and washed with water (250 g), followed by drying, to thereby yield 4.0 g of 4,4′-dihydroxybenzil as a target product.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH:26]1([O:29][C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH2:28][CH2:27]1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=3)[CH:12]=2)[N:7]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH:26]3[CH2:28][CH2:27]3)=[CH:31][CH:32]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: OB(O)c1ccc(OC2CC2)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cn3)cc2c1Cl
Product: O=C(O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC2CC2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 3-chloro-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 36(a)) and 4-cyclopropoxyphenylboronic acid (see Example 40(a)), followed by ester hydrolysis in accordance with Example 1(c).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:20]=[CH:21][CH:22]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:29][C@H:27]1[O:26][C@@H:25]([CH3:30])[CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[CH:18]=2)[CH2:28]1
Reactant: C[C@@H]1CN(c2cccc(Cl)c2)C[C@H](C)O1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
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: C1COCCO1
Solvent: O
Product: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)c1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (1.645 g, 7.91 mmol) was added to a solution of cis-4-(3-chlorophenyl)-2,6-dimethylmorpholine (1.785 g, 7.91 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (1.676 g, 15.82 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (0.914 g, 0.791 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 48 hours. Crude LC/MS showed desired product and only 26% of starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (65i cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (0.74 g, 2.59 mmol, 32.8% yield). LC/MS [M+H]+=272.