Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@@H:11]2[CH2:16][C@H:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13][C@@H:12]2[N:21]2[CH2:26][CH2:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][C:22]2=[O:37])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:40]([BH3-])#N.[Na+].O>CO>[C:1]1([S:7]([CH2:10][C@@H:11]2[CH2:16][C@H:15]([N:17]([CH:18]([CH3:20])[CH3:19])[CH3:40])[CH2:14][CH2:13][C@@H:12]2[N:21]2[CH2:26][CH2:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[CH:23][C:22]2=[O:37])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
A solution of 1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (41 mg, 0.077 mmol) in methanol (1 mL) was treated with aqueous formaldehyde (37%, 0.029 mL, 0.383 mmol) and the mixture was stirred for 45 min. Sodium cyanoborohydride (7 mg, 0.115 mmol) was added, and the mixture stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum to provide the title product (42 mg) as a white glassy solid. MS found: (M+H)+=548.67.
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)[CH3:4])=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH2:5]([N:3]1[CH:1]=[CH:11][C:10]([C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4]1)[CH3:6]
Reactant: C#CC(=O)OCC
Reactant: CN(C=O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(CC)c1
Yield: 65.3 %

Procedure:
Using 117.1 g (1 mol) of N-formylsarcosine, 98.1 g (1 mol) of ethyl propiolate and 638 ml of acetic anhydride, a reaction and post treatment were conducted in a similar manner as in Referential Example 1. The resulting brown oil was distilled under reduced pressure and a 103-104° C. fraction was collected under 4 mmHg, whereby 109.19 g of the title compound were obtained (yield: 71.3%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][OH:19].[OH-].[Na+]>>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:16][CH2:17][CH2:18][OH:19])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1ccnc2cc(C(F)(F)F)ccc12
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 4-chloro-7-(trifluoromethyl)quinoline (1.0 g, 4.7 mmol) and of 2-aminoethanol (0.86 g, 14.1 mmol) is heated, with magnetic stirring, at 150° C. for 15 min and then 185° C. for 30 min. After returning to ambient temperature, the solid is suspended in 5 ml of a 10%, w/v, aqueous sodium hydroxide solution. The precipitate obtained is filtered off through sintered glass, washed with water and then brought to reflux in 10 ml of ethanol for 15 min. After returning to ambient temperature, water is added until a precipitate appears. The precipitate is filtered off through sintered glass, washed with 10 ml of water and then dried under vacuum. The product 10 is obtained in the form of a white powder: 0.82 g (yield=68%). Mp: 181-182° C.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]([CH3:22])[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:3]1.CC(O)=O.CCOC(C)=O>C1COCC1.C(Cl)Cl>[CH3:22][CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[B:4]([OH:5])[OH:3])[C:16]#[C:17][Si:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C#C[Si](C)(C)C)c1ccccc1B(O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 13.93 grams (42.4 mmol, 1.0 eq) of boronate 9 and 27.2 grams (127 mmol, 3.0 eq) of NaIO4 in 126 mL of dry THF was stirred in a 250 mL round bottom flask at room temperature. To this heterogenous mixture was added 42 mL of AcOH (0.5 M). The mixture was warmed to 45° C. and stirred vigorously until complete by TLC (1:1 hexanes:EtOAc). Upon completion (˜65 hours) the mixture was diluted with CH2Cl2 and washed with H2O. The aqueous layer was extracted twice more with CH2Cl2 and the combined organic layers were washed with aqueous Na2S2O3 and then dried over MgSO4. After concentration, the product was purified by filtering through a plug of silica gel with hexane (elutes impurities) followed by EtOAc (elutes product) to give 8.56 grams (81%) of 10 as a colorless oil which is a mixture of boronate esters, Rf 0.20-0.50 (1:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 8.19 (1H, m), 7.82 (1H, m), 7.61 (1H, m), 7.41 (1H, m), 4.96 (1H, m), 1.64 (3H, m), 0.19 (9H, m). 13C-NMR (500 MHz, CDCl3): 151.45, 137.26, 132.98, 127.65, 126.45, 111.05, 85.85, 31.43, 25.84, 0.41. IR (cm−1): 2961 (w), 2164 (w), 1597 (w), 1442 (m), 1345 (s), 1248 (m), 915 (w), 842 (s), 759 (m), 701 (w). HRMS (EI) calcd. for C13H19BO2Si: 246.1247. found: 245.1173 (M-1).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.CO>[C:1]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1c[nH]c2cnccc12
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)c1c[nH]c2cnccc12
Yield: 78 %

Procedure:
Phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (379 mg, 78%) was prepared using phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanol (Example 97) as a yellow solid following the procedure described for Reference Example 13: Rf 0.48 (90:10 methylene chloride/methanol); mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6) δ7.55-7.58 (2H, m), 7.62-7.65 (1H, m), 7.81-7.83 (2H, m), 8.09-8.10 (1H, d, J=5.4 Hz), 8.19 (1H, s), 8.33-8.34 (1H, d, J=5.4 Hz), 8.88 (1H, s), 12.50 (1H, br s); ESI MS m/z 223 [C14H10N2O+H]+; HPLC (Method A) 96.6% (AUC), tR=13.2 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](I)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].B(O)O.[O:25]1[CH2:30][CH2:29][O:28][CH2:27]C1.[OH-].[Na+]>CCOC(C)=O.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>[O:25]1[C:30]2[CH:5]=[CH:6][C:7]([CH:11]=[CH:12][C:8]3[C:7]4[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=3)=[CH:8][C:29]=2[O:28][CH2:27]1
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([N+](=O)[O-])cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccc3c(c2)OCO3)c2ccc([N+](=O)[O-])cc21
Temperature: 90 °C
Yield: 94 %

Procedure:
To a mixture of 6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (4.2 g, 10 mmol), boronic acid (3.46 g, 15 mmol), and Pd(PPh3)4 (0.58 g, 0.5 mmol) at 23° C. under an atmosphere of argon was added 1,4-dioxane (38 mL) and 2N NaOH (aq) (12.5 mL, 25 mmol). The resulting mixture was heated to 90° C. After 2 h the reaction was diluted with EtOAc (100 mL) and water (70 mL), the phases were separated and the organic was extracted 2×100 mL EtOAc. The pooled organic phase was washed with brine (20 mL) then dried with Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with 9:1 hexane:EtOAc) to give 3-(2-benzo[1,3]dioxol-5-yl-vinyl)-6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a yellow solid (4.15 g, 94% yield). FTIR (thin film) 2950, 2898, 1523, 1501, 1483, 1446, 1344, 1249, 1080, 1043, 927 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.56 (dd, 1H, J=0.68, 1.75 Hz), 8.14 (d, 1H, J=1.78 Hz), 8.13 (d, 1H, J=0.67 Hz), 7.50 (d, 1H, 16.53 Hz), 7.25 (d, 1H, 16.52 Hz), 7.18 (d, 1H, J=1.67 Hz), 7.07 (dd, 1H, J=1.65, 8.13 Hz), 6.88 (d, 1H, J=8.0 Hz), 6.05 (s, 2H), 5.84 (s, 2H), 3.66 (t, 2H, J=7.33 Hz), 0.97 (t, 2H, J=7.24 Hz), 0.0 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 148.5, 148.2, 147.0, 143.9, 140.1, 132.7, 131.3, 126.1, 122.3, 121.9, 116.7, 116.5, 108.7, 106.9, 105.7, 101.5, 78.4, 67.2, 17.9, −1.3; LCMS (ESI) [M+H]/z Calc'd 531, found 531.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]2[S:18][C:17]([NH2:19])=[N:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1
Agent: BrBr
Solvent: CC#N
Product: Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To an ice-cold suspension of (3-benzyloxy-5-bromo-phenyl)thiourea (372 g, 1.10 mol) in acetonitrile (6 L) was added dropwise a solution of bromine (65 mL 1.26 mol in 50 mL acetonitrile) over a period of 30 min. The reaction mixture was stirred for 30 min at 0-5° C. then slowly allowed to come to rt, whereby a solid precipitated out. The resulting mixture was stirred at rt for 1 h. After completion of reaction (by TLC), the solid was filtered off and washed extensively with hexane (2×3 L). The solid residue was taken up in ice water, basified with aq. NH3 (pH 10-12) and stirred for 30 min at 5-10° C. The resulting solid was filtered off washed with water and dried under high vacuum to obtain the desired product (216 g, 59%). 1H-NMR (DMSO-d6): δ 5.12 (s, 2H), 6.92 (d, J=2.40 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.30-7.45 (m, 5H) and 7.69 (br s, 2H). LCMS: 334.79 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[S:28][C:27]([CH2:29][OH:30])=[N:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[S:28][C:27]([CH:29]=[O:30])=[N:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CO)s3)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(C=O)s3)[nH]2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of [5-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazol-2-yl]methanol (700 mg) in acetonitrile (10 mL) was added Dess-Martin reagent (796 mg) and the mixture was stirred at room temperature for 15 hr and at 80° C. for 30 min. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was stirred for 20 min. The insoluble material was removed by filtration through celite, and the filtrate was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (700 mg, yield 100%) as a yellow amorphous solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)(C)(C)C>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:22]1[CH2:23][CH2:24][C@@H:20]([NH2:19])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Fc1ccc2nccc(Br)c2c1
Product: N[C@@H]1CCN(c2ccnc3ccc(F)cc23)C1

Procedure:
Starting from 4-bromo-6-fluoroquinoline (commercial) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a yellow solid (212 mg, 43% over two steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([C:36]([F:39])([F:38])[F:37])=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[CH:25]=[N:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=3)=[CH:22][C:21]=2[C:36]([F:37])([F:39])[F:38])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(CCl)cn2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (example 108D]) to give 2-methyl-2-{2-methyl-4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101] to yield the title compound as off-white crystalls of mp. 148–149° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[O:25])[C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:60][O:61][C:62](=[O:67])[C@H:63]([OH:66])[CH2:64][NH2:65].C(N(C(C)C)CC)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:60][O:61][C:62](=[O:67])[C@H:63]([OH:66])[CH2:64][NH:65][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([CH:13]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[O:25])[C:10]2[CH:9]=[CH:8][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](O)CN
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)NC(c1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(C(NC(=O)Nc2ccc(SC(F)(F)F)cc2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
4-[1-(4-Cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoic acid (0.32 g, 0.606 mmol) was dissolved in DMF (7 mL) and HOAt (0.10 g, 0.727 mmol) and EDAC (0.14 g, 0.727 mmol) were added. The mixture was stirred for 30 min. Then (R)-3-amino-2-hydroxypropionic acid methyl ester hydrochloride (0.14 g) and diisopropylethylamine (0.16 mL, 0.909 mmol) were added. The reaction was stirred overnight. The reaction mixture was transferred to a separatory funnel with ethyl acetate (30 mL) and water (15 mL) and extracted. The aqueous phase was extracted once more with ethyl acetate (15 mL) and the combined organic phases were washed with hydrochloric acid (0.2 N, 3×10 mL) and an aqueous solution of saturated sodium chloride (3×10 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified on a column (silica gel, 30 g) using a mixture of ethyl acetate and n-heptane (200 mL, 40:60 and 450 mL 1:1) as eluent to afford 0.33 g of (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(4-trifluoromethylsulfanylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][N:3]=1.FC1C=CN=C(N)C=1OC.Br.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1c(F)ccnc1Br
Agent: Br
Agent: BrBr
Agent: COc1c(F)ccnc1N
Product: Oc1c(F)ccnc1Br
Temperature: 0 °C

Procedure:
2-bromo-4-fluoro-3-methoxypyridine. To a 0° C. solution of 4-fluoro-3-methoxypyridin-2-amine (1 eq.) and 48% HBr (10 eq.) is added bromine (3 eq.) dropwise, followed by the addition of 40% NaNO2 (5.5 eq.). The reaction is stirred at 0° C. until judged complete by TLC. The reaction mixture is adjusted to pH 13 with 50% NaOH (aq). The aqueous solution is extracted with EtOAc. The combined EtOAc layers are dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.800 g, 1.76 mmol), tert-butyl 2-bromoacetate (130 μL, 0.88 mmol) and K2CO3 (0.972 g, 7.04 mmol) in DMF (35 mL) was heated at 80° C. for 2 h. Upon which additional tert-butyl 2-bromoacetate (130 μL, 0.88 mmol) was added, heating at 80° C. was continued for a further 1.5 h. The mixture was allowed to cool to RT and concentrated in vacuo. Diluted with CH2Cl2 and extracted with water (3×). Dried under Na2SO4 and concentrated in vacuo to give tert-Butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.950 g, 1.68 mmol, 95%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[C:12]1([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:13][CH:14]=1)=[O:9]
Reactant: c1ccc2c(OCCN3CCOCC3)cccc2c1
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
To a round bottom flask was added CH2Cl2 (100 mL) followed by the addition of AlCl3 (2.2 g, 16.3 mmol). The suspension was stirred 5 min at room temperature, methylchloroglyoxylate (1.66 mL, 17.88 mmol) was added and stirred an additional 5 min, followed by the addition of 11 (0.841 g, 3.27 mmol). The mixture was stirred at room temperature overnight, quenched with water, neutralized with NaHCO3 and extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent removed leaving a brown oil. The material was purified by column chromatography (0-5% MeOH/CH2Cl2) providing 1.08 g of 12 (97%) as a yellow solid. LC-MS: Calculated mass=343. Observed mass=344.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:22][C:23]=1[CH3:24]>>[CH3:18][C:19]1[N:20]=[C:21]([N:25]2[CH2:26][CH2:27][N:28]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:29][CH2:30]2)[S:22][C:23]=1[CH3:24]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1nc(N2CCNCC2)sc1C
Product: Cc1nc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)sc1C
Yield: 65 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4,5-dimethyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 65%). MS (m/e): 584.3 (M+H+, 100%), 601.4 (M+NH4+, 60%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[K+].OC(CC)CC(O)=O>CO>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CCC(O)CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(O)CC(=O)O

Procedure:
A mixture of 7.0 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate and 1.74 g of 85% KOH in 30 ml ag. methanol was stirred at room temperature for 1.5 hrs. The mixture was concentrated, poured into water and acidified. The product was dissolved in ether, washed with brine, dried over MgSO4 and vacuum evaporated to yield 6.0 of product which was identified as the subject 3-hydroxypentanoic acid.