Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:56][C:57](=[O:60])[CH2:58]Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:37])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:58][C:57]([O:56][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:60])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 6.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester 80 ml of DMF, 4.3 g of cesium carbonate and 2.5 g of Bromo-acetic acid benzyl ester was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 4.4 g.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][NH:12][CH:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)COCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)COCc1ccccc1
Yield: 11.7 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 545 mg of 3-benzyloxy-2-hydroxypropylamine (prepared as described in Preparation 48), 700 mg of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione, 470 mg of sodium cyanoborohydride and 60 ml of anhydrous methanol were used. The resulting crude product was applied to a silica gel chromatography column, and eluted using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 10:1 to 5:1 by volume as the eluent. The resulting product was further purified by reverse phase preparative high performance liquid chromatography [YMC-Pack ODS-A (trade name, manufactured by YMC Co.), using a 50:50:1:1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent], to give 130 mg of the title compound as a pale yellow glassy solid having an Rf value of 0.16 (on silica gel thin layer chromatography, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[CH2:15][C:16]([OH:18])=O)(=[O:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][N:2]1[C:16](=[O:18])[CH2:15][C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[S:3]1(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1sc2ccccc2c1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(=O)Cc2c(sc3ccccc23)S1(=O)=O
Yield: 75.3 %

Procedure:
A solution of 2-[(Methylamino)sulfonyl]-benzo-[b]thiophene-3-acetic acid (450 mg, 1.58 mmoles) and p-toluenesulfonic acid (45 mg) in xylenes (100 ml) was refluxed in a Dean-Stark trap for 6 hours. The solvent was evaporated and the resulting solid recrystallized from isopropanol to give the title compound (318 mg) in a yield of 765, mp 175°-178° C.; ms:m/e 267 (m+,25), 210(8), 160(5), 146(100); 1H-nmr(deuteriochloroform): δ7.96 (m,1H), 7,80 (m,1H), 7.58 (m,2H), 4.22 (s,2H), 3.38 (5,3H); ir (potassium bromide): 1700 cm-1.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:8])=[O:4].Cl.N[CH2:25]C(NC)=O>>[CH3:1][N:2]([CH3:25])[C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:8])=[O:4]
Reactant: CNC(=O)CN
Reactant: CNC(=O)CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Agent: Cl
Product: CN(C)C(=O)CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylcarbamoylmethylamide, substituting 2-amino-N,N′-dimethylacetamide hydrochloride for 2-amino-N-methylacetamide hydrochloride. 1H-NMR (DMSO-d6) δ 8.75 (t, J=4.8 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 6.63 (d, J=9.0 Hz, 2H), 5.18 (s, 2H), 4.11 (d, J=5.4 Hz, 2H), 2.96 (s, 3H), 2.85 (s, 3H); MS LC-MS [M+H]+=315.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[C:31]3[CH3:37])=[CH:4][N:3]=1.Cl>ClCCl.O1CCOCC1>[NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:9]2)=[N:6][C:5]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[C:31]3[CH3:37])=[CH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(-c3cnc(N)c(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(-c3cnc(N)c(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 2-amino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-(3-methyl-1H-indazol-5-yl)pyrazine 109 (20 mg, 0.04 mmol) in dichloromethane (2 mL) was added a 4 M solution of HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-amino-3-[(S)-3-benzylpiperazinyl]-5-(3-methyl-1H-indazol-5-yl)pyrazine 110 (12 mg, 0.03 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[CH3:30])=[O:13]>CCO.[Pd].C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH:21]=[N:22][C:16]=2[CH:15]1[CH3:30])=[O:13]
Reactant: CC1c2ncn(-c3ccc(F)cn3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC1c2ncn(-c3ccc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 48 h
Yield: 62.3 %

Procedure:
To a solution of (2-chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (0.80 g, 1.83 mmol) in degassed EtOH (25 mL) was added 10% palladium on carbon (0.20 mg, 0.19 mmol). The reaction was placed under an atmosphere of hydrogen and let stir for 48 h. The reaction was diluted with DCM and filtered through a pad of Celite®. The solvent was concentrated and chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (500 mg, 62%). 1H NMR (500 MHz, CDCl3) δ 8.45-8.30 (m, 1H), 7.94 (dd, J=18.2, 10.7 Hz, 1H), 7.76 (d, J=5.7 Hz, 1H), 7.67-7.43 (m, 3H), 7.43-7.30 (m, 1H), 5.81 (dd, J=13.3, 6.7 Hz, 1H), 5.07 (d, J=5.6 Hz, 1H), 4.52 (d, J=6.7 Hz, 1H), 3.61-3.31 (m, 1H), 3.08-2.69 (m, 1H), 1.63-145 (m, 3H). MS (ESI): mass calculated for C20H15ClF4N4O, 438.08. m/z found 439.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([NH:10][C:11](=O)[O:12]C1C=CC([N+]([O-])=O)=CC=1)[C:8]#[CH:9]>ClCCl>[CH2:7]([NH:10][C:11]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:12])[C:8]#[CH:9]
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: C#CCNC(=O)N1CCOCC1
Yield: 92.6 %

Procedure:
Morpholine (510 mg, 5.86 mmol) and 4-nitrophenyl prop-2-yn-1-ylcarbamate (800 mg (80% purity), 2.91 mmol) in dichloromethane (10 ml) were stirred at room temperature for 4 hours and then the reaction solution was purified directly by chromatography on silica using ethyl acetate as eluent to give N-prop-2-yn-1-ylmorpholine-4-carboxamide (453 mg, 92%) as a pale yellow solid; NMR Spectrum: (CDCl3) 2.24 (t, 1H), 3.37 (m, 4H), 3.69 (m, 4H), 4.05 (m, 2H), 4.65 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13]([C@H:15]1[C@H:20]([CH3:21])[O:19][C@@H:18]([CH3:22])[CH2:17][N:16]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:14]>>[CH3:11][O:12][C:13]([C@H:15]1[C@H:20]([CH3:21])[O:19][C@@H:18]([CH3:22])[CH2:17][N:16]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:2][C:3]#[C:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[O:14]
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Reactant: ClCC#Cc1ccccc1
Product: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(OCC#Cc2ccccc2)cc1

Procedure:
The title compound was prepared in a manner similar to the preparation in Preparation 3 from (3-chloro-prop-1-ynyl)-benzene and (2S,3R,6S)4-(4-hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. Calculated for C23H25NO6S (M+H): 444.14. Found: 444.0.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.CCOC(C)=O>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: CNc1ccccc1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)C1(C(=O)O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (1.5 g, 11.53 mmol) in THF (24 mL) TEA (1.6 mL, 11.53 mmol) was added dropwise and under stirring thionyl chloride (0.83 mL, 11.53 mmol) and the mixture stirred 30 min at room temperature. A solution of N-methylaniline (1.3 mL, 11.53 mmol) in THF (14 mL) was added dropwise at 0° C. and the mixture was stirred for 2 h. The mixture was diluted with EtOAc, extracted with 2N NaOH, acidified to pH˜2 by addition of 2N HCl and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 246 (1.24 g, 5.66 mmol, 49%) as a white solid. MS (m/z): (M+1) 220.0 (100%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Br:15]Br.OS([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([Br:15])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: BrBr
Reactant: c1ccc(C2CC2)cc1
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
Cyclopropyl benzene (48.5 g, 410 mmol), glacial acetic acid (510 mL), and sodium acetate (38.9 g, 474 mmol) were added to a roundbottomed flask. The flask was cooled in an ice-water bath. A solution of bromine (66.3 g, 414 mmol) dissolved in 105 mL of acetic acid was added dropwise over 90.min. The reaction mixture was stirred at temperatures between 0° C. and 10° C. for 5 h. The reaction was then allowed to warm to rt overnight. Hexanes (1300 mL) and water (250 mL) were added. Aqueous NaHSO3 (1 M) was added until the reaction mixture changed from yellow to clear. The layers were separated. The organic layer was washed with water, 1M aq Na2CO3, and brine, then dried with Na2SO4. The solvent was evaporated and the crude product was purified via sgc using hexanes as the mobile phase to give 17 g of p-cyclopropylbromobenzene (21%) (Compound 44).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][O:10][C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=4[NH:16][C:15]=3[N:14]=[CH:13][CH:12]=2)([CH3:8])[CH2:4][CH2:3]1.[Cl:26]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:26][C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:17]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[C:19]=2[C:11]=1[O:10][CH2:9][C:5]1([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Solvent: CC#N
Product: CN1CCC(C)(COc2c(Cl)cnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of 4-((1,4-dimethylpiperidin-4-yl)methoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.16 mmol), N-chlorosuccinimide (60 mg, 0.45 mmol) in acetonitrile (0.8 mL) and isopropyl alcohol (0.23 mL) was stirred at 40° C. for 16 hours. The reaction mixture was diluted acetonitrile (1 mL) and the solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (12 mg, 20%). 1H NMR (500 MHz, d6-DMSO) δ 9.04 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 4.28 (s, 2H), 2.51-2.46 (m, 2H), 2.28 (m, 2H), 2.22 (s, 3H), 1.82 (m, 2H), 1.51 (m, 2H), 1.19 (s, 3H), NH signal not observed. LCMS (Method D): RT=8.445 min, M+H+=370.1.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[N+:36]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[N+]=[N-].[H][H]>[Pt].CO>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:20]2[NH:19][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([CH2:7][C:6]5[CH:5]=[C:4]([NH2:1])[C:35]([NH2:36])=[CH:34][CH:33]=5)[CH2:13][CH2:12]4)[C:22]=3[N:21]=2)=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(N=[N+]=[N-])c5)CC4)cccc3[nH]2)cc1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc(N)c(N)c5)CC4)cccc3[nH]2)cc1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
In a round bottom flask under nitrogen was combined 4-[4-(3-Azido-4-nitro-benzyl)-piperazin-1-yl]-2-(4-tert-butyl-phenyl)-1H-benzoimidazole (0.19 g, 0.37 mMol), methanol (20 mL), and 5% platinum on carbon (0.145 g, 0.037 mMol). A hydrogen balloon was attached, the flask evacuated, and a hydrogen atmosphere established. After stirring for four hours, the balloon was removed, the flask purged with nitrogen, and the reaction mixture filtered thru Celite with a large excess of methanol. The solution was concentrated to dryness on a rotary evaporator to yield 170 mg (100% yield) of 4-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-benzene-1,2-diamine as a brown oil. LC/MS (Method A), rt=0.90 mins., purity=85.9%, calculated mass=454, [M+H]+=455, [M−H]−=453.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([NH:1][C:2]3[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCC3(CC2)OCCO3)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (5.0 g, 25 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (5.86 g, 37.8 mmol) in dichloroethane (50 mL) was added acetic acid (9.0 g, 150 mmol) and the reaction mixture stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (15.9 g, 752 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to afford the title compound (6.6 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
9.6 g (34.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate and 34.5 ml (233 mmol) of (trifluoromethyl)-trimethylsilane in 343 ml of DMF are mixed with 46.9 g of cesium carbonate at 0° C. It is stirred for 2 hours at 0° C. and then the reaction mixture is added to-water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 10.4 g of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 297 ml of diethyl ether at 0° C. with 2.25 g (59.4 mmol) of lithium aluminum hydride, and it is stirred for 1 more hour at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-50%), 5.6 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained. 12.4 ml (89 mmol) of triethylamine is added to 5.6 g (18.1 mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO, and 11 g (70 mmol) of pyridine/SO3 complex is added in portions over 10 minutes. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after-chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%), 5.9 g of product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[C:5]2[CH3:14]>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:14]
Reactant: Cc1c(C(=O)O)[nH]c2ccc(F)cc12
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cc1c[nH]c2ccc(F)cc12

Procedure:
5-fluoro-3-methyl-1H-indole-2-carboxylic acid (8.49 g, 43.9 mmol) and copper metal (0.35 g, 5.5 mmol) in distilled quinoline (22 mL) was heated to reflux for 3 hours. The copper powder was filtered off and the filtrate was brought to pH 3 at 0° C. with a 6N aqueous solution of hydrochloric acid. The solution was extracted with ether (200 mL) and the organics washed with saturated sodium chloride (200 mL), dried over magnesium sulfate and concentrated in vacuo to give 5-fluoro-3-methyl-1H-indole as a brown solid. MS (ES) m/z 150.0.
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[Cl:12].[Br:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=1>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([C:4]([C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[Cl:12])=[O:13])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1Cl
Reactant: Brc1ccc(Br)nc1
Product: O=C(c1ccc(Br)nc1)c1cc(Br)ccc1Cl

Procedure:
The above N-methoxy-N-methyl-5-bromo-2-chlorobenzamide and 2,5-dibromopyridine were treated in a manner similar to Reference Example 31-(4) to give 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone as a pale yellow solid. APCI-Mass m/Z 374/376 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f18) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:20](=[O:21])[N:19]([CH3:23])[CH3:18])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reaction time: 15 h

Procedure:
A solution of 4-(((3,6-dichloro-2-pyridinyl)methyl)thio)benzenamine (10 grams; 0.035 mole) in 25 ml. of dry pyridine was prepared and dimethyl carbamoyl chloride (3.77 grams; 0.035 mole) added thereto while maintaining the temperature of the reaction mixture at 24°-45° C. The resulting reaction mixture was stirred at ambient temperatures for a period of about 15 hours and then mixed with ice and allowed to stand for a period of about two hours. The aqueous layer was decanted and the residue washed with water and recrystallized twice from ether. As a result of the above operations, the desired N'-(4-(((3,6-dichloro-2-pyridinyl)methyl)thio)phenyl)-N,N-dimethyl urea compound was recovered as a crystalline solid having a melting point of 112°-113.5° C.