Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O:42][CH3:43])=[O:41])=[O:2].[O-:44]Cl=O.[Na+].NS(O)(=O)=O>CC(O)(C)C.O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O:42][CH3:43])=[O:41])([OH:44])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C=O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C(=O)O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of Methyl(1RS,2SR,3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was added a solution of NaClO2 (34 mg, 0.28 mmol) and NH2SO3H (40 mg, 0.42 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 2 h and it was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (Mg2SO4). The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 25% ethyl acetate/hexanes containing 5% of acetic acid) to afford the title compound (90 mg, 69%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:23](=[CH:24][C:25]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=1)[C@:12]1([C@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([OH:20])[C@@H:14]([CH2:21][OH:22])[O:13]1)[CH2:11][CH2:10]2.Cl>C(Cl)Cl.N1C(C)=CC(C)=CC=1C>[C:2](=[O:3])([O:4][CH3:5])[O:22][CH2:21][C@H:14]1[O:13][C@@:12]2([C:23]3[C:9](=[CH:8][C:7]([Cl:6])=[C:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=4)[CH:24]=3)[CH2:10][CH2:11]2)[C@H:17]([OH:18])[C@@H:16]([OH:19])[C@@H:15]1[OH:20]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](COC(=O)OC)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl chloroformate (114 mg, 1.20 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a solution of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-6′-(hydroxymethyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3′,4′,5′-triol (compound AV) (418 mg, 1.00 mmol) in 2,4,6-collidine (5 mL) at −40° C. The whole was stirred at −40° C. for 1 h and at room temperature for 1.5 h. The reaction mixture was poured into ice-cooled 10% HCl and extracted with AcOEt. The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica gel to give the acylated product BH (420 mg, 87%). 1H NMR (CD3OD, 300 MHz) δ 7.25 (s, 1H), 7.23 (s, 1H), 7.09 (m, 4H), 4.05 (s, 2H), 3.80 (m, 1H), 3.65 (s, 3H), 3.62-3.34 (m, 5H), 2.91 (dd, J=6.6, 7.8 Hz, 2H), 2.60 (q, J=7.8 Hz, 2H), 2.55 (dt, J=7.5, 13.2 Hz, 1H), 2.10 (dt, J=7.5, 13.2 Hz, 1H), 1.20 (t, J=7.8 Hz, 3H); MS ESI m/e 477 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(=O)[nH]c2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(=O)[nH]c4)c3)c2cc1OC
Yield: 61.7 %

Procedure:
Following the procedure in Example 115C, phenyl 3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (8 mg, 0.0227 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (8 mg, 0.025 mmol) (prepared as described in Example 113A) to afford 1-(3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (7.8 mg, 0.014 mmol, 62%). 1H NMR (300 MHz, DMSO-d6) δ 12.1 (br s, 1H), 9.03 (br s, 1H), 8.56 (br s, 2H), 7.53-7.26 (m, 7H), 6.91 (d, 1H), 6.43-6.35 (m, 2H), 4.05 (s, 6H), 1.22 (s, 9H); LC-MS (ESI) m/z 556 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)(O)[O-].[Na+].[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18])[N:7]=1
Reactant: OCCNCCO
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCN(CCO)c1nc(Cl)nc(Cl)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
25 Grams cyanuric chloride was dissolved in 145 ml. acetone and the solution poured over 100 grams of ice. Sodium bicarbonate (12.4 grams) was added. While maintaining the temperature at 10°C., diethanolamine (15.5 grams) was added dropwise over a period of about 30 minutes. The temperature was raised to 20°-25°C. and the mixture stirred for about 1 hour. The reaction mixture was filtered, washed witth water and dried to give 31.4 grams of product.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[O:8][CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:9][O:8][C:3]1[S:4][C:5]([CH3:7])=[CH:6][C:2]=1[B:10]([OH:15])[OH:11]
Reactant: COc1sc(C)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1sc(C)cc1B(O)O
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
A stirred mixture of 3-bromo-2-methoxy-5-methylthiophene (Step B, 296 mg, 1.43 mmol) and triisopropyl borate (396 μL, 2.15 mmol) in toluene/THF (2.3/0.6 mL) was cooled to −70° C. under an atmosphere of N2. n-Butyl lithium (2.0M in pentane, 1.07 mL, 2.15 mmol) was added dropwise via a syringe pump over 1 h. The reaction stirred at −70° C. for 40 min more and was quenched with 2N HCl (2 mL) at −20° C. The reaction was partitioned between EtOAc (15 mL) and H2O (15 mL). The aqueous layer was extracted with EtOAc (10 mL); the combined organic layers were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford (2-methoxy-5-methyl-3-thienyl)boronic acid as a yellow oil. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Sc2ccccc2CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Sc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenylthio)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of a saturated sodium chloride solution and dried, providing 2-(4-fluorophenylthio)benzyl cyanide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:27])[C:16](=[O:26])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)[N:19]=2)[C@H:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH3:27][N:15]1[C:16](=[O:26])[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[N:19]=[C:14]1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:28]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of (3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.9 g, 18 mmol) in ethyl acetate (35 ml) was added hydrogen chloride (4N) in ethyl acetate (35 ml) at room temperature. The mixture was stirred at room temperature for 2 hours and was concentrated under reduced pressure. The residue was partitioned between aqueous sodium hydrogen carbonate and chloroform, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford 1-methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (4.6 g, 91%).
Reaction SMILES: C1(=O)OC(=O)C2=CC=CC=C12.[C:12](#[N:21])[C:13]1[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]#[N:16].[NH3:22]>>[NH:16]=[C:15]1[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[NH:22])[NH:21]1
Reactant: N#Cc1ccccc1C#N
Reactant: N
Agent: O=C1OC(=O)c2ccccc21
Product: N=C1NC(=N)c2ccccc21

Procedure:
In the third exemplary process, phthalic anhydride or phthalonitrile and ammonia are primarily reacted to produce an intermediate product such as 1,3-diimino isoindoline, then the intermediate product is reacted with a metal halide in the presence of solvent having a high boiling point.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[H-].[Na+].[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[C:24](Cl)[N:23]=1>CN(C=O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[C:24]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)[N:23]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: N#Cc1cnc(Cl)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ncc(C#N)c(N)n3)CC2)ccc1Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (40.3 mg, 0.15 mmol, 1.2 equiv; intermediate A2) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h 4-amino-2-chloro-pyrimidine-5-carbonitrile (19.3 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.1 mg (35%) of the title compound. MS (ISP): 387.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([O:16][CH:27]([CH3:29])[CH3:28])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)OC(C)C)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (308 mg), 2-iodopropane (0.225 mL), potassium carbonate (312 mg) and N,N-dimethylformamide (2.6 mL) was stirred at 60° C. for 2.5 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (342 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([S:26]C(C)(C)C)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47]Cl)([O-:40])=[O:39]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([S:26][S:47][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N+:38]([O-:40])=[O:39])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SC(C)(C)C)c(Cl)cc3n2COCCOC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(SSc4ccccc4[N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a stirred solution of 1-[5-tert-butylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (3.00 g, 6.42 mmol) and DCM (32 mL) was added potassium carbonate (1.78 g, 12.9 mmol). The reaction mixture was treated with 2-nitrobenzenesulfenyl chloride (3.05 g, 16.1 mmol) and stirred at 23° C. for 16 h. The resulting residue was concentrated and purified by FCC (5-30% EtOAc/hexanes) to provide the titled compound (2.99 g, 82% crude yield) as a 2:1 ratio of regioisomers. This compound was used without further purification in subsequent reactions. MS (ESI/CI): mass calcd. for C23H22ClN5O6S2, 563.1; m/z found, 564.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.85-8.82 (m, 2H), 8.17 (s, 2H), 7.75 (s, 0.66H), 7.72 (s, 1.34H), 7.68 (s, 1.34H), 7.64 (s, 0.66H), 7.45-7.42 (m, 4H), 7.31-7.26 (m, 4H), 6.09 (d, J=2.1 Hz, 4H), 4.36 (q, J=7.1 Hz, 4H), 3.67-3.62 (m, 4H), 3.49-3.42 (m, 4H), 3.31 (d, J=1.9, 6H), 1.38 (t, J=7.1 Hz, 6H).
Reaction SMILES: Br[CH:2]1[CH:10]2[C:5](=[CH:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9]2=[O:11])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:3]1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC>>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[N:15]=3)[CH:3]=[C:2]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CC1(C)C=C2C(C(=O)C1)C(Br)CN2c1cccc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: CC1(C)CC(=O)c2c(-c3nccs3)cn(-c3cccc(-c4nccs4)n3)c2C1
Yield: 13 %

Procedure:
In the same way as described in Example 15, Step 4 using 3-bromo-1-(6-chloropyridin-2-yl)-6,6-dimethyl-1,2,3,4-tetrahydroindol-4-one and 2-tributylstannylthiazole, the title compound (35 mg; 13%) was isolated as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.21 (6H,s), 2.55 (2H,s), 3.24 (2H,s) 7.35 (1H,d, J=3.1 Hz), 7.50-7.53 (2H,m), 7.81 (1H,d, J=3.1 Hz), 7.97-8.02 (3H,m), 8.20 (1H,d, J=7.8 Hz). MS (ES+) 407 (M+1).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].C([Li])CCC.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:5][CH2:1][CH2:2][C:3]#[C:4][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCO[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Into a 1-L three neck round-bottom flask, was placed a solution of but-3-yn-1-ol (20.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (300 mL) and the mixture was purged with nitrogen. The mixture was cooled to −78° C., then n-butyllithium (2.5 M in THF) (270 mL, 2.40 equiv) was added drop-wise followed by the addition of chlorotrimethylsilane (67.9 g, 625 mmol, 2.20 equiv). The resulting mixture was then stirred for 1 h at 25° C., then carefully quenched with aqueous sodium bicarbonate (250 mL). The aqueous was extracted with ether (3×100 mL) and the combined organics was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ether/petroleum ether (1:10-1:1) as the eluent to obtain the title compound as a colorless oil (10.0 g, 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+]>O.Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1/[CH:5]=[CH:13]/[C:14](=[O:15])[CH3:16]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OC)c(/C=C/C(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 16.6 g (0.1 mol) of 2,5-dimethoxybenzaldehyde in 21 ml (0.28 mol) of acetone and 10 ml of water was treated with 2.5 ml of 3N sodium hydroxide solution. The temperature of the reaction mixture should not exceed 30°. The mixture was stirred at room temperature for 20 hours, diluted with water and 3N hydrochloric acid was added to produce a strongly acidic reaction. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained (E)-4-(2,5-dimethoxyphenyl)but-3-en-2-one as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:11]([NH2:19])[NH:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@H:28]([NH2:30])[CH3:29]>CN1C(=O)CCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@H:28]([NH:30][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[C:11]([NH2:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[CH:3]=1)[CH3:29]
Reactant: CSc1nc(Cl)cc(C2=C3N=CC=CN3NC2N)n1
Reactant: C[C@H](N)c1ccc(F)cc1F
Solvent: CN1CCCC1=O
Product: CSc1nc(N[C@@H](C)c2ccc(F)cc2F)cc(-c2c(N)nn3cccnc23)n1
Temperature: 220 °C
Yield: 19.4 %

Procedure:
3-(6-Chloro-2-(methylthio)pyrimidin-4-yl)-1,2-dihydropyrazolo[1,5-a]pyrimidin-2-amine (4b) (500 mg, 1.70 mmoles) was dissolved in 5 mL of NMP along with (S)-1-(2,4 difluorophenyl)-ethylamine (988 mg, 5.0 mmoles, added as the free base). The reaction mixture was heated in the microwave three times at 220° C., for 15 minutes each. The reaction progress was monitored by LC/MS. Upon completion, the reaction was quenched by addition of 1N HCl to the vigorously stirred material until a thick oily material separated. This crude mixture was centrifuged and the thick oil separated. The oily mass was transferred to a round-bottomed flask and methanol was added. Solvents were removed under reduced pressure and the resulting solid was suspended in acetonitrile, warmed to 50° C. and vigorously stirred. Then it was cooled and the resulting precipitate was suction-filtered. The filtrate was reduced to an oil under reduced pressure and then re-dissolved in a minimum amount of methanol and purified via HPLC on C18 silica with acetonitrile/water/TFA as the eluent. After lyophilizing the desired fractions a beige solid was obtained (136 mg, 19.4% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([NH:15][C:16]([NH2:18])=[S:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=C(C2C=CC=CC=2)C2SC(N)=NC=2C=1>>[CH2:1]([O:8][C:9]1[C:14]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[C:12]([O:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1NC(N)=S
Agent: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Product: COc1ccc(OCc2ccccc2)c2sc(N)nc12
Yield: 82 %

Procedure:
Synthesized starting from (5-Benzyloxy-2-methoxy-phenyl)-thiourea in the same manner as described for 5-methoxy-7-phenyl-benzothiazol-2-yl-amine in 82% yield as a beige solid. Mp: 165° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])(=[O:12])=[O:11])([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C.Cl.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=[O:22])(=[O:12])=[O:11]
Reactant: O=C(NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C1CCc2ccccc2C1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccccc1S(=O)(=O)NCCCCCCNC(=O)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of 1,2,3,4-Tetrahydro-2-naphthalencarboxylic acid[6- (2-nitrobenzenesulfonylamino)-hexyl]-amide (0.54 g, 1.17 mmol) in 5 mL of glacial acetic acid stirred at 0° C. was added a solution of tin chloride (1.32 g, 5.88 mmol)in 5 mL conc. HCl and 1 mL of water. The reaction mixture was warmed to room temperature and stirred for 3 h and poured over crushed ice (50 g). The reaction mixture was neutralized with 10% sodium hydroxide and extracted with chloroform (5×50 mL), dried over sodium sulfate and concentrated to afford yellow oil (0.48 g, 95%).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[OH:28][CH2:29][C:30]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:28][CH2:29][C:30]2([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (600 mg, 1.27 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.41 g, 1.40 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (40 μL, 0.26 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate, and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), 1M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 380 mg (50%) as a yellow film. 1H-NMR (CDCl3, 300 MHz) δ 7.96 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.28-7.35 (m, 4H), 7.17-7.23 (m, 1H), 6.86 (m, 1H), 5.62 (s, 2H), 4.93 (q, J=6.2 Hz, 1H), 3.72 (m, 2H), 3.55-3.60 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.34 (d, J=8.8 Hz, 1H), 2.97-3.08 (m, 2H), 2.10-2.21 (m, 2H), 1.91-1.97 (m, 2H), 1.42 (d, J=6.2 Hz, 3H), 1.41 (s, 9H), 0.82-0.87 (m, 2H), 0.08 (s, 9H). Mass spec.: 600.22 (MH)+.