Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.O[C:15]1[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:28])[CH:16]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:28])[CH:16]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(O)c1cccc(Br)c1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-1-pentanol (1.00 g, 4.11 mmol) in dry THF (40 mL) at 0° C. was added ethyl (4-hydroxy-2-methylphenoxy)acetate (865 mg, 4.11 mmol), PPh3 (1.30 g, 4.94 mmol) and ADDP (1.25 g, 4.94 mmol) and the reaction stirred for 30 minutes and then allowed to warm to rt overnight. The mixture was then reduced under vacuum and the residue partitioned between EtOAc and water and the layers separated. The organic layer was washed with water (2×) then brine, dried (Na2SO4) and reduced under vacuum to give a brown oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with petroleum ether 40-60° C.:EtOAc (gradient 1:0 to 9:1) afforded the title compound as colourless oil (1.15 g).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[CH2:21]([Sn+:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH2:31][CH2:32][CH3:33]
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Product: CCCC[Sn](CCCC)(CCCC)OC(=O)Cc1ccc(C(=O)c2ccccc2)cc1

Procedure:
The title product is prepared according to the method as described in example 7 by reacting (4-benzoyl-phenyl)-acetic acid with tri-n-butyltin methoxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[N:32]=[CH:31][NH:30]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:39]([C:35]1[CH:34]=[C:33]2[C:38]([C:29](=[O:28])[NH:30][CH:31]=[N:32]2)=[CH:37][CH:36]=1)(=[O:41])=[O:40]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=c1[nH]cnc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(=O)[nH]cnc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.791 g, 3.16 mmol) in tetrahydrofuran (11.57 ml) was cooled in a dry ice-acetone bath for 5 min. Lithium bis(trimethylsilyl)amide (1M in THF) (3.31 ml, 3.31 mmol) was added drop wise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A solution of perfluorophenyl 4-oxo-3,4-dihydroquinazoline-7-sulfonate (1.18, 3.01 mmol) in THF (12 mL) was added drop wise, and the reaction was stirred for 30 minutes. An additional equivalent of lithium bis(trimethylsilyl)amide (1M in THF) (3.31 ml, 3.31 mmol) was added and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was dissolved in ethyl acetate and loaded onto a silica cartridge, leaving a tan solid on top. The solid was scraped out of the cartridge and set aside. The remaining material was purified by chromatography on a 40-g silica gel column with 0 to 100% EtOAc/Heptane followed by a 10% MeOH/DCM flush. The product containing fractions were concentrated and combined with the previously isolated material to afford N-(2,4-dimethoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-sulfonamide as a tan solid. (ESI) 481.1 (M+Na)+.
Reaction SMILES: [N:1]1([N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH3:15])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Se](=O)=[O:17]>O1CCOCC1>[N:1]1([N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH:15]=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=[Se]=O
Reactant: Cc1nc2ccccc2n1-n1cccc1
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1-n1cccc1

Procedure:
Using the procedure of Example 10B and starting with 1.9 g of 1-(1-pyrrolyl)-2-methylbenzimidazole [Synthesis, 757 (1983)]and 1.07 g of selenium dioxide in 35 ml of dioxane, there was obtained 1.3 g of the product.
Reaction SMILES: [CH3:1][N:2]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.O1CCCC1.[BH4-].[Na+].O>CO>[CH3:1][N:2]([C:14]1[N:15]=[CH:16][CH:17]=[CH:18][N:19]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CCOc1ccc(CO)cc1)c1ncccn1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzaldehyde (16.6 g) in methanol (40 ml)-tetrahydrofuran (40 ml) was added sodium borohydride (1.22 g) in portions at 0° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzylalcohol (15.3 g, yield 91%) as colorless crystals. m.p. 73-74° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+]>CO>[CH:29]1([NH:32][CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30]1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1cccc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (70 mg, 0.19 mmol) and cyclopropanamine (32.55 mg, 0.57 mmol) in anhydrous methanol (10 mL) was stirred at room temperature for 1.5 h. Then the mixture was cooled to 0° C., sodium borohydride (10.82 mg, 0.286 mmol) was added portion-wise. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), extracted with 1N hydrochloric acid (20 mL), the aqueous layer was separated. The organic layer was washed with 1N hydrochloric acid (20 mL). The combined aqueous layers were adjusted to pH=9 with potassium carbonate, extracted with ethyl acetate (25 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to give 9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15 mg, yield 19%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.19-0.29 (m, 4H), 1.74-1.80 (m, 1H), 3.55 (s, 2H), 4.16-4.19 (d, J=8.8 Hz, 1H), 4.60-4.62 (d, J=8.8 Hz, 1H), 6.88-6.90 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 7.01-7.10 (m, 6H), 7.13-7.15 (m, 2H), 7.42-7.44 (d, J=7.6 Hz, 1H), 7.48-7.75 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 408 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.II.[O-][Mn](=O)(=O)=O.[K+].Cl>ClCCl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C:3]([CH2:4][CH3:5])([CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:6][O:7][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CO)(CO)CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: II
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(COS(=O)(=O)c1ccc(C)cc1)(COS(=O)(=O)c1ccc(C)cc1)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
1,1,1-Tris(hydroxymethyl)propane (1; 10.01 g, 74.6 mmol) was added to a stirring solution of pyridine (82.5 mL) at −5° C. p-Toluenesulfonyl chloride (71.04 g, 372.63 mmol) was then slowly added. After 2 hours the reaction was brought to room temperature and stirred for approximately 2 days. The reaction progress was followed by silica gel TLC with dichloromethane (DCM) as the mobile phase and visualized using UV-Vis, iodine, and KMnO4 (ditosylate, Rf≈0.2; 2, Rf≈0.55; p-toluenesulfonyl chloride, Rf≈0.95). The reaction was poured into cold 2 M HCl (600 mL) to precipitate the crude product. The precipitate was washed with several portions of 2 M HCl (3×100 mL), dissolved into ethyl acetate (200 mL), and washed with 2 M HCl (1×50 mL), saturated sodium bicarbonate (3×100 mL), and brine (1×50 mL), dried over anhydrous MgSO4, filtered, and taken to dryness under vacuum to give the product as a white solid. Yield: 42.94 g, 96.5%. 1H NMR (CDCl3; 500 MHz) δ ppm: 0.64 (t, 3H, CH3), 1.35 (q, 2H, CCH2), 2.46 (s, 9H, ArCH3), 3.77 (s, 6H, OCH2), 7.36 (d, 6H, ArH), 7.71 (d, 6H, ArH). 13C NMR (CDCl3 d6; 125.8 MHz) δ ppm: 6.71 (CH3), 21.72 (ArCH3), 21.85 (CCH2), 42.05 (C), 67.81 (OCH2), 128.10 (ArC), 130.23 (ArC), 132.00 (ArC),) 145.52 (ArC). ESI-MS (m/z) 619.30 (619.08 calcd for [M+Na]+ of [C27H32O9S3]). Elemental Anal. calc'd (found) for C27H32O9S3: C, 54.35 (54.40); H, 5.41 (5.47); S, 16.02 (16.12).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][C:20]=1[NH2:29])([CH3:11])([CH3:10])[CH3:9].[Cl:31][CH2:32][C:33](Cl)=O>ClCCl.CO>[C:8]([O:12][C:13](=[O:30])[NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=[C:33]1[CH2:32][Cl:31])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 55.5 %

Procedure:
Triethylamine (9 mL, 64.7 mmol) was added to a solution of tert-butyl[3-(3-aminoquinolin-4-ylamino)propyl]carbamate (13.65 g, 43.1 mmol) in dichloromethane (150 mL). Chloroacetyl chloride (3.8 mL, 47.5 mmol) was added dropwise over a period of 10 minutes. The reaction mixture was stirred at ambient temperature over the weekend and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and 1:1 water:saturated aqueous sodium bicarbonate. The organic layer was washed with brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 14.1 g of crude product as a brown foam. The foam was dissolved in a mixture of dichloromethane (15 mL) and methanol (0.5 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The cartridges were eluted sequentially with 1 L 1:1 ethyl acetate:hexanes, 5% methanol in 1:1 ethyl acetate:hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and concentrated under reduced pressure to provide 8.96 g of tert-butyl[3-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light brown foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([C:14]([OH:16])=O)=[CH:5]2.[NH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1>>[O:23]=[S:20]1(=[O:24])[CH2:21][CH2:22][N:17]([C:14]([C:6]2[N:7]([CH:11]([CH3:12])[CH3:13])[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:16])[CH2:18][CH2:19]1
Reactant: CC(C)n1c(C(=O)O)cc2cc(O)ccc21
Reactant: O=S1(=O)CCNCC1
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(O)ccc21

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 3, the title compound was synthesized from 5-Hydroxy-1-isopropyl-1H-indole-2-carboxylic acid (Example 20, step 3) and thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201). The desired product was obtained in a yield of 75% as white solid. MS (m/e): 335.5 (M−H, 100%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:50]2[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=2)[CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:50]2[S:51][CH:52]=[C:53]([C:55]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:56])[N:54]=2)[CH2:49][CH2:48]1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: O=C(O)c1csc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1csc(C2CC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.34 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g), 2-cyclopropylthiazole-4-carboxylic acid (example 57, step c) (0.12 g) and triethylamine (0.38 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic layer was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.15 g.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[Na]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[CH:4]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CNC
Reactant: CCOC(=O)CC=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
13.1 g (0.29 mol) of dimethylamine were introduced into a suspension of 40 g (0.29 mol) of sodium ethyl formylacetate in 50 ml of toluene and 50 ml of ethanol. HCl gas was then introduced until the point of neutrality was reached and the mixture was stirred at 20° C. for 2 h. After filtering off the precipitate with suction, the mixture was worked up in a customary manner. Ethyl β-dimethylaminoacrylate was obtained in a yield of 91.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:49]=[CH:48][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)(=[O:20])=[O:19])[CH:16]=3)[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)=[O:7])=[C:4]([N:50]([CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)C(=O)C(F)(F)F)[CH:3]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[CH3:88][N:89]([CH3:94])[CH2:90][C:91](=O)[CH3:92]>ClCCl>[F:27][C:25]1[CH:26]=[C:21]([S:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[NH:8][C:6](=[O:7])[C:5]2[CH:48]=[CH:49][C:2]([NH:1][CH:91]([CH3:92])[CH2:90][N:89]([CH3:94])[CH3:88])=[CH:3][C:4]=2[NH:50][CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)(=[O:19])=[O:20])[CH:22]=[C:23]([F:28])[CH:24]=1
Reactant: Nc1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Reactant: CC(=O)CN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CN(C)C)Nc1ccc(C(=O)Nc2n[nH]c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (1.56 g, 1.8 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (2.78 mL, 36 mmol), tetramethylammonium triacetoxyborohydride (710 mg, 2.7 mmol) and 1-dimethylamino-propan-2-one (316 microL, 2.7 mmol). The mixture was stirred at room temperature overnight then additional tetramethylammonium triacetoxyborohydride (710 mg, 2.7 mmol) and 1-dimethylamino-propan-2-one (316 microL, 2.7 mmol) were added. The mixture was heated at reflux and stirred for additional 6 hours. After evaporation of the volatiles, the residue was chromatographed on silica gel eluting with dichloromethane/methanol/triethylamine 90:10:0.1 affording 845 mg of N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-dimethylamino-1-methyl-ethylamino)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide that was dissolved in methanol (5 mL) and triethylamine (2 mL) and stirred at 50° C. for 6 hours. The mixture was then evaporated to dryness and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/30% NH4OH 92:8:0.5 affording 416 mg of the title compound as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[SH-:10].[Na+]>CO>[NH2:8][C:7]1[C:6]([SH:10])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: [SH-]
Reactant: Nc1c(Cl)ncnc1Cl
Agent: [Na+]
Solvent: CO
Product: Nc1c(S)ncnc1Cl
Temperature: 25 °C

Procedure:
The mixture of 4,6-dichloropyrimidine-5-amine (A-2) (16.0 g, 98.2 mmol) and sodium hydrosulphide (7.15 g, 128 mmol) in MeOH (320 mL) is stirred at reflux for 3 h. The reaction is complete based on TLC analysis. The reaction mixture is allowed to cool to RT and then concentrated in vacuo. The residue is poured into aqueous NaOH solution (1M, 200 mL) and then neutralized with acetic acid to adjust the pH to 5-6. The resulting mixture is stirred at RT for 30 min. The solid is collected by filtration, rinsed with water (2×50 mL) and dried in vacuo to afford the product, 5-amino-6-chloropyrimidine-4-thiol (A-3).
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][SiH:7]([CH3:16])[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH2:22][CH:23]=[CH2:24])[CH3:21]>>[C:1]([Si:5]([CH3:17])([CH3:18])[O:6][Si:7]([CH2:24][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])([CH3:16])[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN(C)C
Reactant: C[SiH](O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Product: CN(C)CCC[Si](C)(O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
1,5-Di(tert-butyl)-1,1,3,5,5-Pentamethyltrisiloxane and Karstedt's catalyst (30 ppm) were charged to a 100 mL Schlenk flask. The mixture was heated to 90° C. and N,N-dimethyl allyl amine (4.48 g) was added dropwise via syringe over 5 minutes. After complete addition, the reaction temperature was maintained at 90° C. for 3 hrs and the reaction was monitored by 1HNMR spectroscopy. Upon reaction completion, the volatiles were removed at 100° C./0.1 mmHg, and 15.2 g light yellow oil product was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:15][CH:16]=[CH2:17])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].B1C2CCCC1CCC2.[OH-:28].[Na+].OO>O>[OH:28][CH2:17][CH2:16][CH2:15][C:2]([CH3:18])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: [OH-]
Reactant: C=CCC(C)(C)C(=O)OCc1ccc(OC)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(COC(=O)C(C)(C)CCCO)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate (9.50 g, 38 mmol) and 9-BBN (115 mL, 57 mmol, 0.5 M in THF) was stirred at 60° C. for 60 min, whereupon the reaction mixture was cooled to −5° C. H2O (35 mL) was added, the reaction mixture was stirred for 5 min at −5° C., an aqueous solution of NaOH (35 mL, 3M) was added and the reaction mixture was stirred for a further 10 min at −5° C. An aqueous solution of H2O2 (35 mL, 30%) was added dropwise and the temperature of the reaction mixture was allowed to assume room temperature, whereupon the reaction mixture was stirred for 30 min at room temperature. After evaporation, water (200 mL) was added and the resulting mixture was extracted with CH2Cl2 (5×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1→8% MeOH in CH2Cl2), to give 6.32 g of 4-methoxybenzyl 5-hydroxy-2,2-dimethylvalerate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12](OC)(OC)OC>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[CH3:11]
Reactant: COC(OC)OC
Reactant: Cc1c(Cl)cccc1C(=O)O
Solvent: CO
Product: COC(=O)c1cccc(Cl)c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Alternatively, to a suspension of 3-chloro-2-methylbenzoic acid (6.8 g, 40 mmol) in methanol (40 mL) was added trimethyl orthoformate (4.4 mL, 40 mmol). HCl gas was then bubbled through the suspension for 20 minutes. The resulting solution was then heated in a 60° C. oil bath. After stirring at 60° C. for 16 hours, the solution was allowed to cool to ambient temperature and concentrated under reduced pressure to afford a thick yellow paste. The semi-solid was melted under reduced pressure using a heat gun, and then cooled to afford 3-chloro-2-methylbenzoic acid methyl ester (7.1 g, 95% yield) as a yellow crystalline solid: 1H-NMR (400 MHz, CDCl3): δ 7.70 (1H, d, J=7.8 Hz), 7.51 (1H, d, J=7.8 Hz), 7.17 (1H, t, J=7.8 Hz), 3.91 (s, 3H), 2.60 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([O:23][CH2:24][CH3:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[N+:20]([O-:22])=[O:21].CSC.B(F)(F)F.CCOCC.O>ClCCl>[CH3:1][O:2][C:3](=[O:26])[CH:4]([O:23][CH2:24][CH3:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[N+:20]([O-:22])=[O:21]
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-])C(=O)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: CCOC(Cc1ccc(O)cc1[N+](=O)[O-])C(=O)OC
Yield: 95.1 %

Procedure:
2-Ethoxy-3-(4-benzyloxy-2-nitrophenyl)propanoic acid methyl ester (1.5 g; 4.06 mmole) was dissolved in dichloromethane (8 ml) and dimethylsulfide (8 ml) was added. Boron trifluoride diethyl etherate (5.0 ml; 40.6 mmole) was added under stirring. The reaction mixture was stirred at room temperature for 4 hours and then poured into water and more dichloromethane was added. The phases were separated and the organic phase was washed with water and brine and dried with magnesium sulfate. Evaporation to remove the solvent gave 1.04 g (95% yield) of 2-ethoxy-3-(4-hydroxy-2-nitrophenyl)propanoic acid methyl ester.