Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(=O)C(SC)=CC=C(N(C)C)C(OCC)=O)C=CC=CC=1.F[B-](F)(F)F.[CH3:28][N:29]([CH3:41])[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:32]=[N+](C)C.CC[O-].[Na+].[CH3:46][S:47][CH2:48][C:49]([C:51]1[CH:52]=[C:53]([OH:58])[C:54](=[CH:56][CH:57]=1)[OH:55])=[O:50]>C(O)C>[OH:58][C:53]1[CH:52]=[C:51]([C:49](=[O:50])[C:48]([S:47][CH3:46])=[CH:32][CH:31]=[C:30]([N:29]([CH3:41])[CH3:28])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:57]=[CH:56][C:54]=1[OH:55]
Reactant: CSCC(=O)c1ccc(O)c(O)c1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(O)c(O)c1)N(C)C
Yield: 17.1 %

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (11.4 g), a 2M ethanolic solution of sodium ethylate (60 cc) and 4-[2-(methylthio)acetyl]pyrocatechol (7.9 g) in ethanol (60 cc). After purification on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 6-(3,4-dihydroxyphenyl)-2-dimethylamino-5-methylthio-6-oxo-2,4-hexadienoate (2.4 g), m.p. 144° C., is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH3:19])=O.COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][CH2:17][O:18][CH3:19])/[C:36](=[O:37])[N:38]=1
Reactant: COCCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile (example 77b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2-methoxy-ethoxy)-quinoline-3-carbonitrile. LC-MS m/e 355 (MH+).
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:48][C:49]1[N:54]=[CH:53][C:52]([C@H:55]([NH2:57])[CH3:56])=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:11]=[C:10]([C:21]([NH:57][C@@H:55]([C:52]2[CH:51]=[N:50][C:49]([CH3:48])=[N:54][CH:53]=2)[CH3:56])=[O:23])[CH:9]=1)=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (9.5 mg, 0.069 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.2 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol), N,N-dimethylglycine (40 mg, 0.39 mmol), EDCl (69 mg, 0.36 mmol), HOBt (48 mg, 0.36 mmol), and N,N-diisopropylethylamine (227 μL, 1.30 mmol) in DMF (2 mL) was stirred at rt for 6 h. An additional 0.5 eq. of N,N-dimethylglycine was added and the mixture continued to stir at rt for 16 hr. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water to provide 39 mg (24%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 7.92 (s, 1 H), 7.81 (d, 1 H), 7.66 (s, 1 H), 7.28-7.39 (m, 5 H), 7.15 (dd, 1 H), 6.60 (s, 1 H), 5.67 (s, 2 H), 4.32 (dd, 1 H) 3.33-3.46 (m, 1 H), 3.01-3.20 (m, 4 H), 2.66-2.78 (m, 1 H), 2.19 (s, 6 H), 2.05 (d, 2 H), 1.44-1.75 (m, 2 H); ES-MS m/z 509.23 [M+H]+, HPLC RT (min) 2.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[O:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27]OS(C)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:27][C@@H:23]3[CH2:24][CH2:25][CH2:26][O:22]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(O)cc1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Product: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1

Procedure:
According to method F, N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-hydroxybenzamide was reacted with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester. The product was thus obtained with the molecular weight of 430.35 (C22H24BrNO3); MS (ESI): 430 (M+H+).
Reaction SMILES: [ClH:1].Cl.C(C1C=C(C(N2CCNCC2)CC2(O)CCCCC2)C=CC=1)#C.[C:26]([C:28]1[CH:29]=[C:30]([CH:34]([C:49]2([OH:55])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:35][N:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)[CH:31]=[CH:32][CH:33]=1)#[CH:27]>>[ClH:1].[ClH:1].[C:26]([C:28]1[CH:29]=[C:30]([CH:34]([C:49]2([OH:55])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]2)[CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:31]=[CH:32][CH:33]=1)#[CH:27]
Reactant: C#Cc1cccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)c1
Agent: C#Cc1cccc(C(CC2(O)CCCCC2)N2CCNCC2)c1
Agent: Cl
Product: C#Cc1cccc(C(CN2CCNCC2)C2(O)CCCCC2)c1

Procedure:
In an analogous manner to Example 135, step 4, 1-[1-(3-ethynylphenyl-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(3-ethynylphenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 313 ([M+H]+); HRMS: calcd for C20H28N2O+H, 313.2280; found (ESI, [M+H]+), 313.2280.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1cncc(C2CCCN2)c1
Product: CCCC[C@@H](C(=O)N1CCCC1c1cccnc1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 3-pyrrolidin-2-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[C:21]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([C:21]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(n2ncc(N[C@@H]3C[C@@H]4C[C@H]([C@H]3C)C4(C)C)c(Br)c2=O)CCC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
4-Bromo-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (112.8 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) was mixed with ethyl 1-bromocyclobutanecarboxylate (85.8 μL, 0.53 mmol) and potassium carbonate (73.0 mg, 0.53 mmol) at room temperature and stirred at 150° C. for 2 hours in a microwave reactor. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product containing the desired product was used for the next reaction (222.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>O1CCOCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:6][CH:7]=2)[C:30]=1[N+:31]([O-:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-aminophenyl(methyl)carbamate (36) (7 g, 31.5 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (11.2 g, 31.5 mmol) in dioxane (100 mL) was added Et3N (8 mL) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, the solvent was evaporated before water (200 mL) and EA (100 mL) was introduced. The organic layer was separated and extracted with EA (60 mL×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (37) 9 g as yellow solid (yield 53%). LC-MS (ESI): m/z (M+1) 541.
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[I-:12].[K+].N([O-])=O.[Na+]>C(O)(=O)C.O>[I:12][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: [I-]
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c[nH]nc1I
Yield: 58.6 %

Procedure:
Ethyl 3-amino-1H-pyrazole-4-carboxylate (860.0 mg, 5.54 mmol) was dissolved in acetic acid (5 mL) and water (5 mL). Potassium iodide (921 mg, 5.54 mmol) was added and the mixture was stirred until all solids had dissolved. A solution of sodium nitrite (386 mg, 5.54 mmol) in water (2 mL) was then added dropwise. The reaction was stirred at room temperature for 2 minutes when stirring became hindered due to precipitate formation. Additional water (5 mL) was added and the reaction was allowed to stir overnight. The acetic acid was removed under reduced pressure. The brown residue was taken up in saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated aqueous sodium thiosulfate (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (10-80% ethyl acetate/heptanes) gave the title compound (863 mg, 59%) as a white solid. +APCI (M+H) 267.2; 1H NMR (400 MHz, CDCl3, δ): 12.63 (br. s., 1H), 8.13 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[S:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=2)[C:28](O)=[O:29])[CH2:21][CH2:20]1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][N:33]=[C:25]([N:22]5[CH2:21][CH2:20][S:19][CH2:24][CH2:23]5)[CH:26]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(O)c1ccnc(N2CCSCC2)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccnc(N2CCSCC2)c1
Yield: 50 %

Procedure:
Method Method H2 was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-thiomorpholinoisonicotinic acid to afford the title compound as a light pink solid (93 mg, 50%). 1H-NMR (δ, ppm, DMSO-d6): 2.62 (d, 4H, HThiomorph, J=7.2 Hz), 3.96 (d, 4H, HThiomorph, J=7.2 Hz), 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.93 (dd, 1H, Harom, J=7.9 Hz, J=1.8 Hz), 7.01 (d, 1H, Harom, J=5.1 Hz), 7.19 (s, 1H, Harom), 7.43 (t, 1H, Harom, J=8.2 Hz), 7.60-7.64 (m, 2H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 8.25 (d, 1H, Harom, J=5.1 Hz), 10.39 (s, 1H, NHamide), 11.19 (s, 1H, NHurea), 11.39 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 25.18 (CThiomorph), 47.14 (CThiomorph), 105.01, 106.50, 110.05, 110.75, 113.67, 114.63, 116.26, 130.08, 140.24, 141.28, 143.63, 144.42, 147.04, 148.30, 154.08, 154.64, 158.13, 164.81. HRMS (EI): m/z [M+H] calculated for C22H20N6O3S: 449.1390, found: 449.1396.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: O=C(O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(Br)cc1

Procedure:
5.08 g of 4-bromobenzoyl chloride—prepared by reacting 4-bromobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@H:4]([NH:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:29][CH2:28]1)=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[N:10]=[CH:9]2.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[O:43]=[C:34]1[N:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:25]([NH:24][C@H:4]([CH2:5][C:6]3[CH:7]=[C:8]4[C:12](=[CH:13][CH:14]=3)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])(=[O:17])=[O:16])[N:10]=[CH:9]4)[C:3]([OH:44])=[O:2])=[O:26])[CH2:32][CH2:31]2)[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1
Reactant: COC(=O)[C@@H](Cc1ccc2c(cnn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A solution of (R)-2-{[4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester (775 mg, 1.21 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was cooled to 0° C. A solution of lithium hydroxide monohydrate (115 mg, 4.84 mmol) in water (3 mL) was added. The reaction mixture was stirred at 0° C. for 2 h and then placed in the freezer at −15° C. for 16 h. While cooling the reaction mixture with an ice bath, the pH was increased to ca. 7 by addition of 1N hydrochloric acid (3.8 mL). Organic solvents were removed under vacuum. The resulting aqueous solution was extracted with ethyl acetate after addition of more 1N hydrochloric acid (0.5 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give 684 mg (90%) of the title compound as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ 9.21 (s, 1H), 8.58 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.13-7.09 (m, 2H), 6.88-6.83 (m, 1H), 6.76-6.74 (m, 2H), 4.33-4.27 (m, 2H), 4.18 (s, 2H), 4.09-3.96 (m, 3H), 3.57-3.51 (m, 2H), 3.25-3.04 (m, 2H), 2.74-2.60 (m, 2H), 1.54-1.43 (m, 4H), 0.70-0.64 (m, 2H), −0.08 (s, 9H). Mass spec.: 627 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:2][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:8]([NH2:10])=[O:9])=[CH:13][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(CN[C@H](CC(C)C)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A solution of D-leucinamide hydrochloride (2.8 g, 16.8 mmol), and p-anisaldehyde (2.29 g, 16.8 mmol) in methanol (150 mL) was treated with anhydrous ZnCl2 (538 mg, 5 mmol). The resulting suspension was then treated with NaCNBH3 (1.05 g, 16.8 mmol) portion wise and heated at reflux for 3 h. The reaction was cooled to rt, quenched with saturated NaHCO3 (3 mL), diluted with EtOAc (500 mL), and washed with brine. Concentration afforded the crude benzyl amine as a white wax, which was carried on without further purification (3.57 g, 84%). MS (ESI), (M+H)+ 251.4; 1H NMR (CDCl3) δ 7.20 (d, 2H, J=6.6), 7.10 (br s, 2H), 6.88 (d, 2H, J=8.4), 5.30 (br s, 1H), 3.80 (s, 3H), 3.63 (dd, 2H, J=4.5, 12), 1.44-1.65 (m, 3H), 0.95 (d, 3H, J=6.3), 0.80 (d, 3H, J=6.3).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:25]=[C:24]3[C:19]([O:20][CH2:21][CH2:22][N:23]3[S:26]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[O:36][CH3:37])(=[O:28])=[O:27])=[N:18][CH:17]=2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C>Cl>[Cl:35][C:33]1[CH:32]=[CH:31][C:30]([O:36][CH3:37])=[C:29]([S:26]([N:23]2[C:24]3[C:19](=[N:18][CH:17]=[C:16]([C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([OH:38])=[O:5])=[CH:8][CH:9]=4)=[O:15])[CH:25]=3)[O:20][CH2:21][CH2:22]2)(=[O:28])=[O:27])[CH:34]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ncc(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: Cl
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ncc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 86.8 %

Procedure:
4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carbonyl]-amino}-benzoic acid tert-butyl ester (27 mg, 48 μmol) was dissolved in hydrogen chloride solution (4 M in 1,4-dioxane, 1.0 mL) and stirred at room temperature for 4 days, then the precipitate was collected by filtration and washed with ethyl acetate to produce the title compound (21 mg, 86%). White solid, MS (ISP)=502.0 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]([NH2:29])[CH3:28])[CH:23]=[CH:24][C:25]=1[F:26].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([NH:29][CH:27]([C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)[CH3:28])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[NH2:1])=[CH:7][CH:8]=1
Reactant: CC(N)c1ccc(F)c(F)c1
Reactant: COc1ccc(C(=O)c2ccccc2N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccccc2N)cc1
Yield: 59.6 %

Procedure:
In a similar manner to that described in Example (1a), 2-amino-4′-methoxybenzophenone (2.12 g), 1-(3,4-difluorophenyl)-ethylamine hydrochloride (2.60 g), triethylamine (7.8 ml), titanium tetrachloride (1.1 ml), sodium cyanoborohydride (2.34 g) and acetic acid (0.8 ml) were reacted, to afford a mixture of diastereomers of the title compound (2.05 g) as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])C=C.[C:20]1(C)[CH:25]=C(C)C=C(C)[CH:21]=1>>[CH2:25]([C:10]1[CH:9]=[CH:8][C:7]([F:11])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1Cl
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1ccc(F)c(-c2ccc(Cl)cc2Cl)c1O
Yield: 65 %

Procedure:
A solution of 2′-allyloxy-2,4-dichloro-6′-fluorobiphenyl (1.7 g, 5.7 mmol) in mesitylene (50 mL) was refluxed for 48 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 1.1 g (65%) of 3-allyl-2′,4′-dichloro-6-fluorobiphenyl-2-ol as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][N:20]([CH3:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:25]=[CH:26][C:21]([N:20]([CH3:30])[CH3:19])=[CH:22][CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1
Yield: 52.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-dimethylaminophenylboronic acid (129 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 17 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 119 mg (53%) of the title compound as an amorphous foam. mp 197°-202°. FDMS: m/e=348. α[D]589 =+76.84 (c=0.95, chloroform).