Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH2:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2.[CH3:37][CH:38]1[NH:43][CH2:42][C:41]2[S:44][C:45]([C:47]([O-])=[O:48])=[N:46][C:40]=2[CH2:39]1.[Li+].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:47]([C:45]3[S:44][C:41]4[CH2:42][NH:43][CH:38]([CH3:37])[CH2:39][C:40]=4[N:46]=3)=[O:48])[CH:25]([CH2:29][CH2:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH2:24]1)(=[O:21])=[O:22])=[CH:5]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1)N1CCNC(CCCc2cccs2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CCCc3cccs3)sc2CN1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
In N,N-dimethylformamide (15 ml) were dissolved 1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-[3-(thien-2-yl)propyl]piperazine (257 mg), lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (129 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg) and 1-hydroxybenzotriazole hydrate (76.4 mg). Under ice cooling, diisoproylethylamine (180 μl) was added dropwise to the resulting solution, followed by stirring at room temperature for 15.5 hours. The reaction mixture was extracted with methylene chloride and water. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (2% methanol—methylene chloride) using as a carrier silica gel. After conversion into the corresponding hydrochloride by the addition of 1N aqueous hydrochloric acid in ethanol, methylene chloride-methanol-ether was added to solidify the hydrochloride. The resulting solid was purified again by subjecting it to thin-layer chromatography (10% methanol—methylene chloride), followed by the addition of 1N aqueous hydrochloric acid in ethanol to form the corresponding hydrochloride. Methylene chloride-methanol-ether was added to solidify the hydrochloride. The resulting solid was collected by filtration, washed with ether and then dried, whereby the title compound (62.6 mg) was obtained as colorless powder.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][C@H:6]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C@H:4]1[C:13]([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Br:22][CH2:23][C:24](F)=[O:25].[Si](F)(C)(C)C>ClCCl>[Br:22][CH2:23][C:24]([N:3]1[CH2:7][C@H:6]([O:8][Si:9]([CH3:10])([CH3:11])[CH3:12])[CH2:5][C@H:4]1[C:13]([O:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:25]
Reactant: O=C(F)CBr
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1[Si](C)(C)C
Agent: C[Si](C)(C)F
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CBr
Temperature: 25 °C
Yield: 95 %

Procedure:
Into a solution of trimethylsilyl (2S,4R)—N-(trimethylsilyl)-4-(trimethylsilyloxy)-pyrrolidine-2-carboxylate (6.95 g, 20.0 mmol) in 15 ml of anhydrous dichloromethane was drop wise added a solution of bromoacetyl fluoride (2.82 g, 20.0 mmol) in 5 ml of dichloromethane with vigorous stirring at room temperature. Exothermic reaction occurred with liberation of Me3SiF. The reaction mixture was stirred at room temperature for 2 h and then the reaction mixture was evaporated to dryness at reduced pressure, which gave 7.53 g (yield 95%) of trimethylsilyl (2S,4R)—N-(bromoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate as off-white solid: 1H-NMR (CDCl3) δ 0.04 (m, 9H), 0.21 (m, 9H), 1.80-2.4 (m, 2H), 3.3-3.6 (m, 1H), 3.61-3.80 (m, 2H), 4.3-4.6 (m, 2H); 13C-NMR (CDCl3) δ −0.27 (CSi), −0.01 (CSi), 26.94, 38.04, 55.71, 59.26, 70.33, 165.28, 171.82.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](O)=[O:24])=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]2[CH:19]=[CH:20][C:15]([CH3:26])=[CH:16][CH:17]=2)=[N:8]1
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: Cc1ccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-p-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=348.31.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3].[Li+].CC([N-]C(C)C)C.[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1COCC1.C(OCC)(=O)C.O>[C:8]([O:7][C:6](=[O:12])[NH:5][S:2]([CH2:1][P:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:28])(=[O:4])=[O:3])([CH3:9])([CH3:11])[CH3:10]
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)CP(=O)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
To a solution of tert-butyl methylsulfonylcarbamate (2 g, 10 mmol) in THF (25 mL) at −78° C. was added LDA (2 M in THF, 15.4 mL, 30.7 mmol). Upon completion of addition, the reaction mixture stirred for 10 min and then diphenylphosphinic chloride (2.42 g, 10.2 mmol) was added drop wise to the reaction at −78° C. After 90 min, water (100 mL) was added and the reaction mixture was diluted with ethyl acetate (250 mL). The aqueous layer was adjusted to pH 5 with 5% aqueous HCl. The white precipitate that formed was filtered and the solid dried in vacuo to give tert-butyl(diphenylphosphoryl)methylsulfonylcarbamate (2.9 g, 72% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]12[CH2:9][N:8](C(OCC)=O)[CH2:7][CH:6]1[N:5]([CH3:15])[CH:4]([CH3:16])[CH2:3]2.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]12[CH2:9][NH:8][CH2:7][CH:6]1[N:5]([CH3:15])[CH:4]([CH3:16])[CH2:3]2
Reactant: CCOC(=O)N1CC2N(C)C(C)CC2(Cl)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1CC2(Cl)CNCC2N1C

Procedure:
7.6 g (30.8 mmol) of ethyl 5-chloro-2,3-dimethyl-2,7-diazabicyclo[3.3.01octane-7-carboxylate are heated under reflux overnight with 30 ml of concentrated hydrochloric acid. The mixture ic concentrated, the residue is taken up in 30 ml of water, and the mixture is rendered alkaline with potassium carbonate, extracted five times with 50 ml of chloroform each time, dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [NH2:1][C:2](=[S:12])[C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:6][CH:7]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CC(C)=O>[C:17]1([C:15]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:6][CH:7]=3)[S:12][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(C(N)=S)cs1
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)cs1
Temperature: -10 °C
Yield: 90 %

Procedure:
To a solution of 150 mg (0.745 mmol) of methyl 4-(aminothioxomethyl)-thiophene-2-carboxylate (as prepared in the previous step) in 6 mL of acetone was added 148 mg (0.745 mmol) of 2-bromoacetophenone. After refluxing for 2 h, the mixture was concentrated by boiling to a volume of ca. 2 mL. The resulting mixture was cooled (−10° C.) and filtered washing with cold acetone (2×0.5 mL). A second crop was obtained from the mother liquors and the combined crops dried to afford the title compound as a beige solid (202 mg, 90%). 1H-NMR (300 MHz, DMSO-d6) δ8.56 (d, 1H, J=1.5 Hz), 8.25 (d, 1H, J=1.5 Hz), 8.18 (s, 1H), 8.04 (d, 2H, J=7 Hz), 7.48 (t, 2H, J=7 Hz), 7.38 (t, 1H, J=7 Hz), and 3.89 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C15H11NO2S2: 302.0 (M+H). Found: 301.8.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:11][C@@H:10]2[N:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:27]([Cl:39])=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:40])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][N:7]1[CH2:11][C@@H:10]2[N:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:27]([Cl:39])=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:40][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Acryloyl chloride (1M in THF, 0.225 mL, 0.22 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-6-methoxybenzene-1,3-diamine (Intermediate 35, 105 mg, 0.21 mmol) and DIPEA (0.041 mL, 0.24 mmol) in CH2Cl2 (3 mL), which was cooled in an ice/water bath. The mixture was stirred for 0.5 h, washed with brine and then concentrated in vacuo. Purification by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (60 mg, 52%) as a pale yellow solid; 1H NMR: 1.77-1.81 (1H, m), 1.95-2.16 (5H, m), 2.24-2.35 (1H, m), 2.38-2.48 (1H, m), 2.86-2.90 (1H, m), 3.18-3.22 (1H, m), 3.37-3.45 (1H, m), 3.76 (3H, s), 4.33-4.37 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.51 (1H, dd), 6.66 (1H, s), 7.10 (1H, dt), 7.33-7.41 (1H, m), 7.65 (1H, s), 8.3-8.4 (2H, m), 8.56 (1H, s), 8.81 (1H, d), 8.94 (1H, s), 9.38 (1H, s); m/z: ES+, MH+ 545.57.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=O.[CH2:13]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][NH:34][CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH2:14][CH2:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN1C(=O)CCC1.CO>[NH2:29][C:21]1[C:20]2[N:30]=[C:17]([CH2:13][CH2:14][CH2:15][CH3:16])[N:18]([CH2:31][CH2:32][CH2:33][N:34]([CH2:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=3)[CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[C:19]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC1CCN(C)CC1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)O)cc1)C1CCN(C)CC1
Temperature: 50 °C

Procedure:
A solution of 2-(4-formylphenyl)acetic acid (0.14 g) dissolved in NMP (10 mL) was added to a stirred solution of the product from example 8 step (i) (0.34 g) in NMP (10 mL) at rt. Sodium triacetoxyborohydride (0.90 g) was added and the mixture heated at 50° C. for 24 h. The resulting solution was dissolved in methanol (0.5 mL), acidified with acetic acid (0.5 mL) and and purified by SCX. The crude product was further purified by RPHPLC to give the subtitle product, yield 0.25 g.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(SCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 57 %

Procedure:
Prepared analogously to Example 10 from 1-methyl-2-[(4-amidinophenyl)methylthio]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 57% of theory, C26H25N5O3S (487.58) Rf value: 0.23 (Reversed Phase silica gel RP-8; Methanol/5% saline solution=6:4) ##EQU93##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2ccccc2c1
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
100 g (0.63 mol) of 2-methoxynaphthalene were dissolved in 1.2 l of acetic acid and, at 10° C., 100 ml of 65% strength nitric acid were slowly added dropwise. The mixture was then stirred at 10° C. for 2 h. The resulting precipitate was then filtered off with suction to yield 72.5 g (57%). Melting point 129°-130° C.
Reaction SMILES: [CH:1]1C2C(=O)NC3C=CC=CC=3NC=2C=CC=1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30](=[O:37])[NH:29][C:28]3[CH:38]=[CH:39][CH:40]=[CH:41][C:27]2=3)=[O:25])=[CH:19][CH:18]=1>>[CH3:1][N:17]1[CH2:18][CH2:19][C:20]([CH2:23][C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30](=[O:37])[NH:29][C:28]3[CH:38]=[CH:39][CH:40]=[CH:41][C:27]2=3)=[O:25])=[CH:21][CH2:22]1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: O=C1Nc2ccccc2N(C(=O)Cc2ccncc2)c2ccccc21
Product: CN1CC=C(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 4-pyridioacetic acid chloride hydrochloride via 5,10-dihydro-5-[(4-pyridinyl)acetyl]-11H-dibenzo[b,e]-[1,4]diazepin-11-one and 5,10-dihydro-5-[(4-pyridinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepin-11-one methoiodide.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)(O)=[O:2].Cl.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:43]([CH2:42][NH:41][C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)=[O:2])(=[O:44])[NH2:45]
Reactant: NCC(N)=O
Reactant: O=C(O)CCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)CCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.6 %

Procedure:
2-[3-(3-Carboxypropoxy)-4-phenylbenzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (50 mg), glycinamide hydrochloride (17 mg), 1-hydroxybenzotriazole (29 mg) and triethylamine (47 mg) were suspended in N,N-dimethylformamide (2 mL) at room temperature. To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (36 mg), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (23 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc21
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c(cc2Cl)N(C)C(=O)CC3)c1
Temperature: 120 °C
Yield: 30 %

Procedure:
A mixture of 7-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.06 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 26 mg, 0.09 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.2 mg, 0.006 mmol) and sodium carbonate (2 N aq., 0.06 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title product (7.1 mg, 30%) as a white solid. MS, 394.2 (M+H+)+.
Reaction SMILES: [CH:1]([OH:5])([CH2:3][CH3:4])[CH3:2].[Na].[Br:7][CH2:8][CH2:9][CH:10]([CH3:14])[CH2:11][CH2:12]Br>>[Br:7][CH2:8][CH2:9][CH:10]([CH3:14])[CH2:11][CH2:12][O:5][CH:1]([CH2:3][CH3:4])[CH3:2]
Reactant: CC(CCBr)CCBr
Reactant: CCC(C)O
Agent: [Na]
Product: CCC(C)OCCC(C)CCBr
Reaction time: 2 h

Procedure:
To 115 g (1.56 mols) of sec-butanol are added over the course of 15 minutes, 2.0 g (0.087 mol) of finely cut sodium. The mixture is stirred at 60° for 2 hours in order to dissolve the sodium completely. After the addition of 21.2 g (0.087 mol) of 1,5-dibromo-3-methylpentane, the mixture is stirred at 60°, over the source of 18 hours. The precipitated sodium bromide is filtered off and the excess sec-butanol is distilled off. The residue is taken up in 300 cc of ether, washed three times with water and once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated at 40° /20 mm Hg. After chromatography of the residue on silica gel with hexane/ethyl acetate (98,5:1,5) and subsequent fractional distillation in a high vacuum, 1-bromo-5-sec-butoxy-3-methyl-pentane is obtained as a colourless liquid. B.P.: 104° - 106°/13 mm Hg
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:34])[F:35])=[CH:32][C:27]=4[C:26]([F:25])([F:40])[F:41])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(F)(F)F)cc1C(F)(F)F
Yield: 5 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2,4-bis(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 129 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,4′-bis-trifluoromethyl-biphenyl-2-carboxylic acid (7 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.27-8.37 (m, 2H), 8.05-8.15 (m, 3H), 7.77 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](C(O)=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)[C:16]([Cl:18])=[O:17]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:16]([Cl:18])=[O:17])=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (820 mg, obtained in Example 116, step 5) in CH2Cl2 (10 mL) were added two drops of DMF and oxalylchloride (0.58 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (555 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (49 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (5 mL) was added. The mixture was cooled in an ice bath and a solution of 2-bromomethyl-1-chloro-4-methoxy-benzene (1.0 g, [CAS Reg. No. 3771-13-9]) in 1,2-dimethoxyethane (5 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=6:4) to give the title compound as a colorless solid (510 mg, 36%). MS (neg. ion, m/e)=330.3 [(M−H)−].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:16](=[O:17])[NH:15][C:14]3[N:18]=[CH:19][CH:20]=[CH:21][C:13]=3[S:12]2(=[O:23])=[O:22])[CH:6]=[N:7][C:8]=1[O:9][CH3:10].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27]O.CN(C(/N=N/C(N(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC1C=C(N2C(=O)N(CC3C(C)=CC(F)=CN=3)C3C=CC=CC=3S2(=O)=O)C=C(OC)N=1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:26]=1[CH2:27][N:15]1[C:14]2[N:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12](=[O:22])(=[O:23])[N:11]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]1=[O:17]
Reactant: COc1cc(N2C(=O)Nc3ncccc3S2(=O)=O)cnc1OC
Reactant: OCc1c(F)cc(F)cc1Cl
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: COc1cc(N2C(=O)N(Cc3ncc(F)cc3C)c3ccccc3S2(=O)=O)cc(OC)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3Cl)c3ncccc3S2(=O)=O)cnc1OC
Yield: 80 %

Procedure:
The title compound (118 mg, 0.24 mmol) was prepared from 2-(5,6-dimethoxypyridin-3-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (IntF4) (101 mg, 0.30 mmol), 2-chloro-4,6-difluorobenzyl alcohol (IntA22) (59 mg, 0.33 mmol), TMAD (103 mg, 0.6 mmol) and triphenyl phosphine (157 mg, 0.6 mmol) in DCM (3 mL) using the methods of (162).