Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.ClCCl>CC(C)=O>[CH:26]1([NH:29][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CS(=O)c1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Fc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1

Procedure:
A solution of 2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (430 mg, 90%, ˜1.1 mmol) in cyclopropylamine (4 mL, 57.7 mmol) was heated at 45° C. in a sealed glass tube for 6 hours. The excess cyclopropylamine was removed in vacuo to provide crude N-cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (370 mg, 97%). A small portion of the crude material was chromatographed (19:1 dichloromethane:acetone to 9:1 dichloromethane:acetone) to provide material as a light yellow solid. Rf 0.26 (9:1 dichloromethane:acetone); 1H NMR (CDCl3) δ 8.52 (d, 1H), 8.42 (d, 1H), 8.29 (d, 1H). 8.21 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 7.32 (s, 1H), 6.98 (t, 1H), 6.48 (d, 1H), 5.69 (br, 1H), 2.81 (m, 1H), 0.83 (m, 2H), 0.61 (m, 2H); MS m/z 347 (M+1).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:11]12[CH2:12][CH2:13][CH:14]([CH:9]=[CH:10]1)[CH:5]1[CH:6]2[C:1](=[O:8])[CH:2]=[CH:3][C:4]1=[O:7]
Reactant: C1=CCCC=C1
Reactant: O=C1C=CC(=O)C=C1
Solvent: c1ccccc1
Product: O=C1C=CC(=O)C2C3C=CC(CC3)C12

Procedure:
A solution of 40 g of 1,4-benzoquinone and 35 mL of 1,3-cyclohexadiene in 90 mL of benzene was stirred in a closed vessel for 3 days at rt. The reaction mixture was concentrated and the residue was crystallized in EtOH to obtain 57 g of the desired compound as mixture of stereoisomers as greenish solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][CH:14]1[CH2:16][CH2:15]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:13][CH2:14][CH2:15][CH3:16]
Reactant: Cn1c(C(=O)NC2CC2)cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCc1cc2ccccc2n1C
Yield: 32.8 %

Procedure:
To a solution of 1-methyl-N-cyclopropylindole-2-carboxamide (2.1 g, 9.8 mmole) in dry THF (40 mL) was added dropwise a solution of 1.0 M LiAlH4 in THF (2.2 mL, 22 mmole). The reaction mixture was heated at reflux overnight, then was cooled and quenched with 10% NaOH. The mixture was filtered and the filtrate was concentrated in vacuo. Flash chromatography on silica gel (5% MeOH/CH2Cl2) gave the title compound (0.65 g, 33%) as a viscous oil: MS (ES) m/e 203 (M+H)+.
Reaction SMILES: [C:1]1(=[O:14])[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][NH:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:2]1[C:1](=[O:14])[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3]1
Reactant: O=c1[nH]nc2n1-c1ccccc1OC2
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(CCCCl)nc2n1-c1ccccc1OC2

Procedure:
A solution of 2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one, from step 3 above (14.0 g., 0.074 mole), in 500 ml. of N,N-dimethylformamide (DMF) under a nitrogen atmosphere was treated with 3.91 g. (0.081 mole) of a 50% mineral oil suspension of sodium hydride and warmed on a steam bath for 0.5 hour. The resulting mixture was cooled in an ice bath, treated dropwise with 8.68 ml. (0.081 mole) of 1-bromo-3-chloropropane, and the resulting mixture was stirred 18 hours at room temperature to insure complete reaction and then concentrated in vacuo. The residue was mixed with cold water, extracted with methylene chloride, washed with dilute sodium chloride brine solution, dried over sodium sulfate and concentrated. The residue was chromatographed on 1000 g. of silica gel using 25% ethyl acetate in Skellysolve®B hexane (25:75, v/v) mixture. The product thus obtained was crystallized from ethyl acetate/Skellysolve®B hexanes, as described above to give in two crops 12.09 g., m.p. 77°-78° C., and 3.05 g., m.p. 76°-78° C., of the above subtitled intermediate product. The analytical sample had a melting point of 77.5°-78.5° C.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:20])[O:8][CH2:7][C@@H:6]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][N:5]2[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][CH2:2][C:3]1([CH3:20])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(C)(CI)OC[C@@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CI)CN2CCNC[C@H]2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
(9aS)-tert-butyl 3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (108 mg, 0.273 mmol) was taken up in DCM (3 mL) and TFA (0.42 mL, 5.45 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH. The solution was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and rinsed with MeOH, then 7N NH3/MeOH solution to release the product. The solvent was removed in vacuo give (9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (79 mg) as an orange oil.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([OH:30])([C:22]3=[O:29])[CH2:20]1)[CH2:26]2>>[C:1]([O:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([OH:30])([C:22]3=[O:29])[CH2:20]1)[CH2:26]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C1C2CC3CC(O)(C2)CC1(O)C3
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C1)C(=O)C(O)(C3)C2
Yield: 87 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1,3-dihydroxyadamantane-4-one was used instead of the 1-hydroxyadamantane-2-one, and, as a result, a 1-acryloyloxy-3-hydroxyadamantane-4-one (yield: 87%, white solid) was produced.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:20]([CH3:21])[CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
The compound (22 g, 48 mmol) obtained in Step 3 was dissolved in dimethylformamide (60 ml), imidazole (3.9 g, 57.7 mmol) and tert-butyldimethylsilyl chloride (8.0 g, 53.0 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (200 ml), washed successively with water (twice) and saturated brine, and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:7 to 4:6) to give 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (25 g, yield 92%) as a white wax.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:26]1[N:27]=[CH:28][C:29](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[CH:30][CH:25]=1
Reactant: Cc1ncccc1Br
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)cn1
Yield: 31.9 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60.2 mg, 0.2 mmol) and 3-bromo-2-methylpyridine (34.4 mg, 0.2 mmol) in DMF (1.5 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a light yellow solid (25 mg, 25%). NMR indicated 6% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 7.74 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.78 (d, J=16.8 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.49 (s, 1H), 7.07-7.00 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.55 (t, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.34 (t, J=8.4 Hz, 1H, partially overlapping with MeOH residue), 2.78 (s, 3H), 2.23 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.18 (dd, J=8.8 Hz, J=4.8 Hz, 1H); MS ESI 393.1 [M+H]+, calcd for [C25H20N4O+H]+ 393.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O:24]C)[O:22][CH3:23].C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:21]([O:22][CH3:23])=[O:24])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 94.7 %

Procedure:
Into a 25 ml, three-necked round-bottom flask fitted with a thermometer, vigreux column, distillation head, magnetic stirrer, syringe pump and nitrogen sweep was charged 5.0 g of 3-(4-benzyloxyphenoxy)-2-butanone and 10 g of dimethyl carbonate, and the solution heated to 90° C. Thereafter, 2.0 ml sodium methoxide in methanol was added over a period of 50 minutes via a syringe pump. At the end of this addition, the reaction mixture was of a thick, cloudy orange consistency. It was then stirred for 40 minutes and charged with another 2.7 ml of sodium methoxide in methanol over a period of 30 minutes while distilling over methanol. At the end of the addition, the solution was very thick, and another 5 ml of dimethylcarbonate was added to improve the stirring capabilities. The solution was then removed from the heat, cooled to room temperature, and allowed to set for one hour. After this time, it was reheated to reflux temperature, and another 1.1 ml of sodium methoxide in methanol was charged over a period of 13 minutes. Fifteen minutes after the addition, the heat was removed, and the solution cooled to room temperature. The solution was then stripped to remove dimethyl carbonate and then mixed with 50 ml of ethyl acetate, 50 ml of ice water and 5 ml of acetic acid. The resulting mixture was shaken and separated and the organic phase was washed with 50 ml of water, and dried over magnesium sulfate. The solution was then filtered and stripped on an aspirator, yielding 5.75 g of a dark brown oil which was identified as being the subject compound by suitable analysis.
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([O:15][CH2:16][CH3:17])(=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][Ge:2]([Cl:4])([Cl:3])[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][C:5]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: Cl[GeH](Cl)Cl
Product: CCOC(=O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 36 g (0.2 mol) of trichlorogermane and 35.2 g (0.2 mol) of ethyl cinnamate was stirred for 2 hours, and then the reaction product was distilled under vacuum to afford 56 g of a fraction, b.p. 169°-170° C./4 mmHg. Yield 78.7%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH:31][C:32]1[CH:36]=[C:35]([CH2:37][CH2:38][C:39](O)=[O:40])[O:34][N:33]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:31][C:32]1[CH:36]=[C:35]([CH2:37][CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[O:40])[O:34][N:33]=1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)CCc1cc(O)no1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C2CCN(C(=O)CCc3cc(O)no3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 25 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (46.8 mg, 0.112 mmol), 3-(3-hydroxy-isoxazol-5-yl)-propionic acid (17.7 mg, 0.112 mmol), triethylamine (47 uL, 0.337 mmol) and BOP (47.6 mg, 0.112 mmol) in 1 mL DMF were reacted as above. The crude product was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[3-(3-hydroxy-isoxazol-5-yl)-propionyl]-piperidin-4-yl}-phenyl)-amide as a white solid (15.5 mg, 25%). ES-MS calcd for C28H25F3N4O5 (m/e) 554.53, obsd 555 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][CH2:46]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:46][CH2:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: OCCc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCc3ccccn3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 40 h
Yield: 12.1 %

Procedure:
To a solution of N-[1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.58 mmol), 2-pyridinethanol (71 mg, 0.58 mmol) in THF (5 ml) were added triphenylphosphine (152 mg, 0.58 mmol), and diethyl azodicarboxylate (101 mg, 0.58 mmol), and the mixture was stirred at room temperature for 40 hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:5) and thin layer chromatography to give the title compound (43 mg, 0.07 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: NC(=O)C1CCNCC1
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: NC(=O)C1CCN(CCCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (100 mg, 0.23 mmol) and piperidine-4-carboxamide (36.0 mg, 0.28 mmol). The title compound was afforded as a solid (20.0 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.85 (1H, m), 8.42 (1H, s), 7.21 (1H, m), 6.73 (1H, m), 3.19 (2H, m), 2.84 (2H, m), 2.25 (1H, m), 2.0 (1H, m), 1.8 (2H, m), 1.64 (4H, m), 1.53 (2H, m), 1.23 (1H, m). MS m/z: 518.33, 520.35 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:23](B(O)O)=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][N:26]=[CH:25]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]([N:8]1[CH2:20][CH2:19][C:11]2[N:12]=[C:13]([C:23]3[C:22]([CH3:21])=[CH:30][CH:29]=[C:28]4[C:24]=3[CH:25]=[N:26][NH:27]4)[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2[nH]ncc2c1B(O)O
Reactant: COc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
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: COCCOC
Product: COc1nc(-c2c(C)ccc3[nH]ncc23)nc2c1CN(Cc1ccccc1)CC2
Temperature: 140 °C

Procedure:
A mixture of 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.09 g, 3.75 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (600 mg, 3.41 mmol), Pd(PPh3)4 (197 mg, 0.170 mmol), and Na2CO3 (2 M, 5.97 mL, 11.9 mmol) in DME (11 mL) was heated in a microwave reactor at 140° C. for 1.5 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (20-100% EtOAc/heptane) to provide 6-benzyl-4-methoxy-2-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 386.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2-c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2ncccc2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 4-[2-(4-fluorophenyl)-pyridin-3-yl]-piperazine-1-carboxylic acid t-butyl ester (0.9 g, 2.52 mmol) in DCM (25 mL). Add trifluoroacetic acid (8.6 g, 5.8 mL, 75.6 mmol). Stir the mixture at room temperature for 2 hr. Purify by a SCX ion-exchange column to give the title preparation. MS (ES): m/z=258 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>CN(C=O)C.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>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:3][C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(-c3cccnc3)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3ccccn3)cc(-c3cccnc3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5-bromo-7-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.20 g, 0.53 mmol) in DMF (5 mL) was added 2-tributylstannyl pyridine (0.23 g, 0.53 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.061 g, 0.053 mmol). The reaction mixture was then again degassed and heated at 120° C. for 8 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (80:20) to provide the title compound as off white solid (0.012 g, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:9].CO.[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][C:3]=1[NH2:9]
Reactant: Nc1ccc(Cl)c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
35.8 g of 4-chloro-1,3-diaminobenzene are stirred thoroughly into 250 ml of water and 50 ml of methanol. 23 ml of methanesulphonyl chloride are added dropwise at 0° C. in the course of about 2 hours; the pH is kept at 4 by dropwise addition of concentrated sodium hydroxide solution. The mixture is subsequently stirred at room temperature for about 2 hours and, if appropriate after diluting with water, the 1-chloro-2-amino-4-methanesulphonamido-benzene which has separated out is then filtered off. It is sufficiently pure for further reactions according to Example 59.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl.N1C=CC=CC=1>[C:27](=[O:28])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of 2-[4-(6-Chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 104, 3.90 g, 10.6 mmol) in dichloromethane (20 mL) and pyridine (2 ml) was added dropwise phenyl chloroformate (1.6 mL, 12.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography eluting with hexane/ethyl acetate (3:1) afforded 4.2 g (82%) of the title compound as a colorless syrup.