Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:22])=[C:11]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10]([CH3:22])=[C:11]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1cccc(OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cccc(O)c1C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 3-(3-(benzyloxy)-2-methylphenyl)acrylate (5.00 g) in methanol (100 mL) was added 10% palladium-activated carbon (500 mg), and the mixture was stirred for 15 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.50 g) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[C:10]1[N:11]=[C:12]([O:36][CH3:37])[C:13]([N:16](COCC[Si](C)(C)C)[S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])(=[O:19])=[O:18])=[N:14][CH:15]=1>>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[C:12]([O:36][CH3:37])=[N:11][C:10]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)=[CH:15][N:14]=1)(=[O:19])=[O:18]
Reactant: OCC1CCNCC1
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(N2CCC(CO)CC2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 55 using 4-(hydroxymethyl)piperidine (0.4 g) and N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.3 g). Yield 0.012 g.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:6].P(=O)(O)(O)O.Cl>O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[N:1][OH:3])[CH3:12]
Reactant: CCOC(=O)CC#N
Reactant: O=N[O-]
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)=NO
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A solution of sodium nitrite (57.30 g, 830.60 mmol) in water (710.00 ml) was treated with ethyl cyanoacetate (100.00 g, 884.00 mmol). 85% Orthophosphoric acid (36.60 ml, 540.00 mmol) was added dropwise over 45 min, while keeping the temperature of the reaction mixture below 35° C. with the aid of an ice bath. At the end of the addition, the mixture was warmed to 40° C. and stirred for 1 hour. The reaction was quenched at 45° C. with fuming HCl (73.90 ml, 880.00 mmol), and the mixture was then left to cool to room temperature and at 0° C. overnight to complete precipitation. The solid was filtered, the filtrate washed with water and dried under high vacuum overnight to yield 70 g of cyano-hydroxyimino-acetic acid ethyl ester as white crystals. A second batch was obtained by extracting the mother liquor with ether (44.00 g, total yield 91%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](O)(=[O:10])[CH:7]([CH3:9])[CH3:8]>O>[CH3:8][CH:7]([CH3:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: c1ccsc1
Reactant: CC(C)C(=O)O
Solvent: O
Product: CC(C)C(=O)c1cccs1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture containing thiophene (10.1 g, 120 mmol), isobutyric acid (8.8 g, 100 mmol) and 20 g of polyphosphoric acid was magnetically stirred at 75° C. for 2 hours. The reaction mixture was diluted with water (100 ml) and extracted with CH2Cl2 (2×). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield a brown oil: 14 g (77%) GC-MS: M=154.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:29](O)=[O:30])[CH2:12]1)(=[O:10])=[O:9].[CH2:32]([NH:36][C:37](=[O:45])[C:38](=[O:44])[C@@H:39]([NH2:43])[CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37](=[O:45])[C:38](=[O:44])[C@@H:39]([NH:43][C:29]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:15][N:14]1[C:16]([C:18]1([C:21]2[C:26]([F:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=2)[CH2:20][CH2:19]1)=[O:17])=[O:30])[CH2:40][CH2:41][CH3:42])[CH2:33][CH2:34][CH3:35]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1
Reactant: CCCCNC(=O)C(=O)[C@@H](N)CCC
Product: CCCCNC(=O)C(=O)[C@H](CCC)NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ncc(Cl)cc2F)CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-hexanoic acid butylamide in step 1. MS (m/e)=669.17 [M+H+].
Reaction SMILES: [N:1]1([C:7]([NH:9][C@@H:10]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]([C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][CH2:45][NH2:46])[CH2:38][CH:39]([CH3:41])[CH3:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:42]([CH2:47][OH:48])[CH2:43][CH2:44][CH2:45][NH:46][C:11]([C@@H:10]([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-[(morpholine-4-carbonyl)-amino]-3,3-diphenyl-propionic acid and amine intermediate VII. The final product was obtained in 36% yield. Rf=0.15 EtOAc 100%.
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:17]=1)=[O:15])[CH3:12].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([N:8]3[CH2:9][CH2:10][C:6]4([O:5][CH2:4][CH2:3][CH2:2][O:1]4)[CH2:7]3)=[C:22]([F:27])[CH:23]=2)[N:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:17]=1)=[O:15])[CH3:12]
Reactant: C1COC2(CCNC2)OC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(N3CCC4(C3)OCCCO4)c(F)cc2c1=O
Temperature: 45 °C

Procedure:
Into oven-dried glassware under a N2 atmosphere were placed 0.176 g (1.23 mmol) of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2, then 0.300 g (0.82 mmol) of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (preparation described by H. Narita, et al., Yakugaku Zasshi, 106(9), 795-801, 1986; CA106:196218) dissolved in 10 mL of pyridine, and 0.46 mL (3.28 mmol) of triethylamine. The solution was then heated at 45° C. for 24 hours. The solvent was removed by evaporation to afford the title product which was purified by column chromatography over silica gel (0.5% methanol/chloroform increasing to 2.0% methanol/chloroform). The ester was not further purified, but was taken directly to the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>COCCOC>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH:21][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1)[CH3:17]
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCO3
Reactant: CCN(CC)CCN
Solvent: COCCOC
Product: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Yield: 75.1 %

Procedure:
A solution of chloride 206 (250 mg, 1.12 mmol) and N1,N1-diethylethane-1,2-diamine (0.63 mL, 4.48 mmol) in DME (25 mL) was stirred at reflux temperature for 2 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (5-10%) of MeOH/DCM to give the 1-oxide 209 (255 mg, 75%) as a yellow solid: mp 150-151° C.; 1H NMR δ 8.09 (t, J=1.6 Hz, 1H, H-9), 6.79 (s, 1H, H-5), 5.90 (br s, 1H, NH), 4.72 (t, J=8.3 Hz, 2H, H-7), 3.48-3.54 (m, 2H, CH2N), 3.30 (dt, J=8.3, 1.4 Hz, 2H, H-8), 2.69-2.72 (m, 2H, CH2N), 2.59 (q, J=7.1 Hz, 4H, 2×CH2), 1.05 (t, J=7.1 Hz, 6H, 2×CH3); 13C NMR δ 166.5, 159.3, 151.8, 129.3, 126.3, 116.6, 102.1, 72.9, 51.3, 46.7 (2), 38.7, 28.6, 11.7 (2). Anal. calcd for C15H21N5O2.¼CH3OH: C, 58.8; H, 7.1; N, 22.5. Found: C, 58.8; H, 6.7; N, 22.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH3:18][CH:19]([CH3:25])[C:20](=O)[CH2:21][C:22]#[N:23]>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH:19]([CH3:25])[CH3:18])[C:21]([C:22]#[N:23])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: CC(C)C(=O)CC#N
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Product: CC(C)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (prepared as described in example 91 step A) and 4-methyl-3-oxo-pentanenitrile. Light yellow solid. MS (ESI): 341.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COC1CCCC1.O.CCO.O.COC1CCCC1>[NH2:35][C:34]1[CH:36]=[CH:37][C:31]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COC1CCCC1
Product: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3)nc(N3CCOC[C@@H]3C)c2C1
Temperature: 100 °C
Yield: 89.5 %

Procedure:
(S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) (1.0 g, 3.06 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (805 mg, 3.67 mmol), Pd(PPh3)2(Cl)2 (107 mg, 0.15 mmol) and Na2CO3 (487 mg, 4.59 mmol) were stirred in CPME/Water/EtOH (14/1/6 mL) under nitrogen for 5 mins, followed by heating at 100° C. overnight. The reaction mixture was then diluted with water and CPME, and precipitate collected by filtration to give 1.05 g of a brown solid. A portion of the brown solid was further purified by prep. HPLC to give 32.6 mg of an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.Cl.[N:24]1([C:29](N)=[NH:30])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[NH:1]([CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2)[C:29]([NH2:30])=[NH:24]
Reactant: N=C(N)n1cccn1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C

Procedure:
N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, 1H-pyrazol-1-carboxamidine hydrochloride and diethyl isopropylamine are dissolved in DMF, and the reaction mixture is heated to 100° C., then cooled and diluted by addition of of water. The aqueous mixture is extracted with EtOAc, and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to give N-(5-Guanidinomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide. 5-Guanidinomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH3:1][C:2]1[N:7]2[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a mixture of crude tert-butyl {1-[4-(5-methyl-3-phenylimidazo[1,2-a]pyridin-2-yl)phenyl]cyclobutyl}carbamate (49 mg) in DCM (0.42 mL) and methanol (0.26 mL) was added a solution of 4 M hydrogen chloride in dioxane (0.54 mL) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted three times with a mixture of DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo to give 16 mg of the title compound in 42% overall yield.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][S:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[OH:19][CH:18]([C:17]1[CH:20]=[CH:21][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: CSc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(SC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 8.4 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 69 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 13 ml (0.1 mol) of 4-(methylthio)benzaldehyde in 100 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained methyl 4-hydroxy-4-[4-(methylthio)phenyl]-2-butynoate as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:14]([CH3:15])=[N:13][N:12]=[C:11]2[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)[CH3:9])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:11]([C@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)=[N:12][N:13]=[C:14]2[CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1nnc([C@H]2CCCN2C(=O)OC(C)(C)C)n1[C@@H](C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc([C@H]2CCCN2)n1[C@@H](C)c1ccc(Cl)cc1

Procedure:
A solution of the Boc-protected triazole product of Step C (1 g) in 40 ml of 40% TFA/DCM was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and used directly as the TFA salt in the next step. MS: calculated: 290.13. Found (MH+): 291.3
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[F:16][C:17]([F:23])([F:22])[CH2:18][C:19](=O)[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:20][C:19]1([CH2:18][C:17]([F:23])([F:22])[F:16])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: CC(=O)CC(F)(F)F
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(CC(F)(F)F)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 4,4,4-trifluoro-2-butanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 2 h at 70° C. in a sealed tube. The mixture was heated to 80° C. After 3 days, the mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate-hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0249 g, 15%) as a yellow solid:
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:17])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:17][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1n[nH]c2cc(Br)ccc12
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2cc(Br)ccc12
Temperature: 3 °C
Reaction time: 12 h

Procedure:
1.07 cm3 of crotonyl chloride are added to 2 g of 6-bromo-1H-indazole-3-amine, prepared previously, in 30 cm3 of pyridine, cooled to about 3° C. The medium is allowed to return to about 19° C. over 12 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 20 cm3 of ethyl acetate and 20 cm3 of distilled water. The aqueous phase is re-extracted with 20 cm3 of ethyl acetate. The aqueous phases are combined and then evaporated under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 130 mg of N-(6-bromo-1H-indazol-3-yl)-2-butenamide (E form) are obtained in the form of a beige-coloured solid melting at 232° C.
Reaction SMILES: [K+].[Br-].[F:3][C:4]([F:22])([O:7][C:8]([F:21])([F:20])[C:9]([F:19])([F:18])[C:10]([F:17])([F:16])[O:11][C:12]([F:15])([F:14])[F:13])[CH2:5][OH:6].[O-]Cl.[Na+].S(=O)(=O)(O)[OH:27]>CC1(C)N([O])C(C)(C)CCC1.O.CC#N>[F:3][C:4]([F:22])([O:7][C:8]([F:20])([F:21])[C:9]([F:18])([F:19])[C:10]([F:16])([F:17])[O:11][C:12]([F:13])([F:14])[F:15])[C:5]([OH:27])=[O:6]
Reactant: OCC(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: O=S(=O)(O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 25 °C
Yield: 87 %

Procedure:
5.5 mL water, 16 ml MeCN, 0.32 g KBr, TEMPO (0.11 g), and 8 g of 2,2-difluoro-2-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-ethanol are placed in a 100 ml glass flask equipped with a dropping funnel and stirrer. 43 mL of 15% (wt) aq. NaOCl buffered to pH 8-9 were added via the dropping funnel in 3 portions over two days while stirring at room temperature. Concentrated sulphuric acid and water were added to bring the pH to about 1 to 2. The reaction mixture was extracted three times by diethyl ether and the combined ether phases were dried over magnesium sulphate. The solvent was evaporated to give colorless liquid, which was distilled using a water pump (15 mmHg, 70° C.) to give 7.25 g of the acid. Yield: 87%. 1H NMR (CDCl3): 9.39 (s, 1H); 19F NMR (CDCl3): −56.28 (t, J=8.7 Hz, 3F); −79.19 (t, J=11.9 Hz, 2F); −84.58 (m, 2F); −86.86 (m, 2F); −130.45 (m, 2F).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:26]([OH:27])[OH:25])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 73.8 %

Procedure:
4-Bromo-octyloxybenzene (Compound 6, 31.5 g, 0.111 mol) was dissolved in 300 mL tetrahydrofuran. The solution was cooled to −78° C. in a cooling bath and n-butyllithium (55.3 mL of 2.5M solution, 0.138 mol) was added to it. After stirring for 25 minutes at −78° C., triisopropylborate (36.4 g, 0.194 mol) was added quickly with a syringe. The cooling bath was removed, and 90 minutes later, the solution was re-cooled to 0° C. 150 mL of a dilute HCl solution was added. After 30 minutes, ethyl ether was added to the reaction mixture and the organic layer was washed with water (2 times), dried with MgSO4, and concentrated to provide an oil, which slowly crystallized over time. This crystallized product was re-crystallized once from acetonitrile to provide a colorless solid, 4-octyloxy-phenylboronic acid (Compound 7, 20.5 g, 74%).
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:40]([CH3:41])=[CH:39][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.CO.[OH-].[Na+]>C1COCC1>[NH:38]1[C:34]([C:30]2[CH:29]=[C:28]([C:24]3[CH:23]=[C:22]([C:20]4[S:21][C:17]5[C:16]([C:42]6[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=6)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:40]([CH3:41])=[CH:39][C:18]=5[N:19]=4)[CH:27]=[CH:26][N:25]=3)[CH:33]=[CH:32][CH:31]=2)=[N:35][N:36]=[N:37]1
Reactant: Cc1cc2nc(-c3ccnc(-c4cccc(-c5nnn[nH]5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4cccc(-c5nnn[nH]5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of crude (S)-2-(2-(2-(3-(1H-tetrazol-5-yl)phenyl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate from the previous reaction (assume 0.027 mmol) in THF (0.4 mL) and methanol (0.4 mL) was added NaOH (0.4 mL of a 2N solution). The reaction mixture was heated at 40° C. for 2 h, cooled, quenched with NH4Cl (sat. aq.), and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give the crude product which was used without further purification. LCMS-ESI+: calc'd for C32H30ClN6O2S: 597.2 (M+H+); Found: 597.0 (M+H+).