Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>Cl.CO.O>[O:24]1[CH2:23][CH2:22][N:21]([CH:18]2[C:13]3[C:12]4[CH:11]([CH:10]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:9][C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:19]2)[CH2:26][CH2:25]1
Reactant: O=C(c1ccccc1)N1c2cccc3c2C(CCC3N2CCOCC2)C1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: c1ccc(C2Nc3cccc4c3C2CCC4N2CCOCC2)cc1
Yield: 89.9 %

Procedure:
A portion (0.56 g) of the compound obtained in Example 134 was dissolved in a solution (15 ml) of 10% hydrochloric acid in methanol and to the solution was added 6N hyrdochloric acid (15 ml). The mixture was heated to reflux for 3 hours and allowed to cool. The reaction mixture was diluted with water, adjusted to pH 9 with potassium carbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent to yield 0.38 g (90%) of the titled compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C[O:14][C:15](=O)[C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18].C(O)(=O)C>C1COCC1.O>[CH3:19][C:16]([CH3:20])([CH2:17][CH3:18])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCC(C)(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Yield: 50 %

Procedure:
Dimethyl methylphosphonate (9.3 g, 0.075 mol) was dissolved in anhydrous THF (80 ml) under argon atmosphere. To the solution stirred at -78° C. was added dropwise n-butyl lithium (1.61N, 47 ml, 0.075 mol) over 30 minutes, and then a solution of 2,2-dimethylbutanoic acid methyl ester (3.9 g, 0.03 mol) in anhydrous THF (10 ml) was also added dropwise over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Under ice cooling, acetic acid (4.5 ml) and water (10 ml) were added to the mixture. After concentration, water (20 ml) was added to the residue, and the mixture was then extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxo-pentylphosphonate (3.36 g, 0.015 mol, yield: 50%, b.p.=115-117/0.5 mmHg). The structure was identified by the following data.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16]Br)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nc(CBr)cs1)N(C1CCCCC1)C1CCCCC1
Reactant: Sc1ccccn1
Product: O=C(Nc1nc(CSc2ccccn2)cs1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (L) from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl)urea and 2-mercaptopyridine.
Reaction SMILES: [C:1]([N:5]1[C@@H:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@@H:8]2[O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)(C)(C)C.C(O[C@H:28]1[NH:31][C:30](=[O:32])[C@@H:29]1[C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:36]([O:35][C@@H:33]([C@@H:29]1[C@@H:28]([C@@H:2]([CH3:3])[C:1]([N:5]2[C@@H:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@@H:8]3[O:7][C:6]2=[O:17])=[O:4])[NH:31][C:30]1=[O:32])[CH3:34])([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=O)N1C(=O)O[C@H]2Cc3ccccc3[C@H]21
Agent: CC(C)(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)O[C@H]2Cc3ccccc3[C@H]21
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
Under a nitrogen atmosphere, 231 mg (1. 0 mmol) of 3-propionyl-(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.75 ml (2.2 mmol) of a tetrahydrofuran solution (0.8M) of t-butylmagnesium chloride was slowly added dropwise at room temperature. After the resulting mixture was allowed to react for 20 minutes under the same conditions, the reaction mixture was cooled to 5° C. and added with 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one at the same temperature. After stirring for 10 minutes, 10 ml of ethyl acetate was added to the reaction mixture, followed by the dropwise addition of 2ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 83 mg (0.18 mmol) of a condensation product was obtained (yield: 18%, β:α=64:46).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].C1C(=O)N(Br)C(=O)C1.[NH2:25][C:26]([NH2:28])=[S:27]>O>[NH2:28][C:26]1[S:27][C:4]([C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[O:6])=[C:3]([C:2]([F:16])([F:15])[F:1])[N:25]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: O
Product: Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Temperature: 85 °C

Procedure:
A mixture of 4,4,4-Trifluoro-1-(4-fluoro-phenyl)-butane-1,3-dione (15 g, 64 mmol) and NBS (11.4 g, 64.1 mmol) was ground together at RT, which incited to give a homogeneous mixture and then solidified to give crude brominated product. Water was added to rinse the solid. The solid was taken up in ethanol (50 mL), and thiourea (4.9 g, 64 mmol) was added. The mixture was heated at 85° C. for 4 h, cooled to RT and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 291.0 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.Cl.[F:34][C:35]1[CH:48]=[CH:47][C:38]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH:42]([CH3:46])[CH2:41]2)=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]/[C:18]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][C:38]2[CH:47]=[CH:48][C:35]([F:34])=[CH:36][CH:37]=2)[CH2:41][CH:42]1[CH3:46])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1/C=C/C(=O)O
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)/C=C/c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
(E)-3-(2-tert-Butyloxycarbonylamino-5chlorophenyl)-acrylic acid (1.0 g, 3.36 mmol) and EDCl.HCl (645 mg, 3.36 mmol) and racemic 1-(4-fluorobenzyl)-3-methyl-piperazine (Bolos, Jordi et al. J. Med. Chem. (1996), 39(15), 2962-2970) (770 mg, 3.7 mmol) were dissolved in CH2Cl2 (34 ml) and stirred at room temperature for 4 hours. The reaction mixture was purified via chromatography (SiO2, EtOAc/hexanes 1/1) to yield the title compound as colorless foam (1.2 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)C(=O)OC(C)(C)O[C:12]2=[O:20])=[CH:6][CH:5]=1.[Br:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.C(OCC)(=O)C.CCCCCC>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:12](=[O:20])[NH:37][C:36]2[CH:38]=[CH:39][C:33]([Br:32])=[CH:34][CH:35]=2)[CH:21]2[CH2:22][CH2:23][CH:24]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:25][CH2:26]2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(CC2(C3CCC(C(C)(C)C)CC3)C(=O)OC(C)(C)OC2=O)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CC(C(=O)Nc2ccc(Br)cc2)C2CCC(C(C)(C)C)CC2)cc1
Reaction time: 0.13 h

Procedure:
To 1 eq (2.32 mmol) of 4-[5-(4-tert-Butyl-cyclohexyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester was added 1.5 eq (3.5 mmol) of 4-bromoaniline in 2 mL of n-methyl-pyrrolidinone in a microwave vial. The reaction was run for eight minutes at 220 degrees C. The reaction mixture was worked up by partitioning with ethyl acetate/diethyl ether (1:1)/1 N HCl. Product was isolated by chromatography gradient: 10% ethyl acetate/hexane to 40% ethyl acetate hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]=[C:7]([C:12]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=O)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2].[NH2:23]/[C:24](/[CH3:30])=[CH:25]\[C:26]([O:28][CH3:29])=[O:27]>>[CH3:30][C:24]1[NH:23][C:12]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)/C=C(/C)N
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)C(OC)OC
Product: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Yield: 60.3 %

Procedure:
A mixture of methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.19 g) and methyl 3-aminocrotonate (6.50 g) was heated at 60° to 63° C. for 6 hours and at 100° to 105° C. for 4 hours and 45 minutes. The resulting crystalline mass was triturated with methanol and collected by filtration to give crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (12.04 g). Thus obtained crystals (1.07 g) were recrystallized from methanol (5 ml) to give pure crystals (0.93 g), m.p. 132° to 133° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH:34]([C:44](O)=[O:45])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[N:47]1[CH:52]=[CH:51][C:50]([C:53]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([NH2:62])[CH:60]=3)[N:55]([C:63]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=2)=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:38]1([CH:36]2[CH2:35][CH:34]([C:44](=[O:45])[NH:62][C:59]3[CH:60]=[C:61]4[C:56](=[CH:57][CH:58]=3)[N:55]([C:63]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)([C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]=[C:53]4[C:50]3[CH:51]=[CH:52][N:47]=[CH:48][CH:49]=3)[CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccccc2)C1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (49 mg, 0.129 mmol) was added to a suspension of 1-(tert-butoxycarbonyI)-5-phenylpiperidine-3-carboxylic acid (36 mg, 0.117 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.117 mmol) in DMF (0 5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19](O)=[O:20].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:19]([C:3]1[C:4]([CH:16]([CH3:18])[CH3:17])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:20]
Reactant: CC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Reactant: Nc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 6.3 g of the product of Step E, 2.1 g of 2-aminothiazole, 4.74 g of dicyclohexylcarbodiimide and 130 ml of dimethylformamide was stirred for 72 hours and was then filtered. The filtrate was evaporated to dryness and the residue was taken up in 50 ml of a 5% sodium bicarbonate solution. The mixture was filtered and washed with water until the wash water were neutral to obtain 8 g of raw product. The latter was chromatographed and was eluted with a 9-1 methylene chloride-ethyl acetate to recover the fraction with an Rf = 0.25. The product was dried to obtain 6 g of product which was crystallized from acetone to obtain 4.2 g of N-(3-thiazolyl)-4-hydroxy-2-isopropyl-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 213° C.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:30](=O)[CH2:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(OCC)(=O)C>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (56.0 mg, 0.137 mmol) in 1,2-dichloroethane was treated sequentially with propionaldehyde (0.01 mL, 0.1 mmol) in 1,2-dichloroethane and acetic acid (0.1 mL, 2 mmol), stirred at ambient temperatures under nitrogen for 2 hours, treated with additional propionaldehyde (0.1 mL, 1 mmol) to aid in solubility, stirred at ambient temperatures for 1.5 hours, treated with sodium triacetoxyborohydride (59.8 mg, 0.283 mmol), stirred for 1.25 hours at ambient temperatures, diluted with ethyl acetate and poured into excess 1.0 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo at 81° C. for 20 minutes to yield 3-(1-naphthylsulfonyl)-5-(1-propylpiperidin-4-yloxy)-1H-indazole as a light orange solid, 50.4 mg (81.8% yield). The solid was dissolved in chloroform and methanol, treated with ethereal HCl and concentrated in vacuo at 82° C. for 15 hours to give the title product as a light orange semi-solid, 40.2 mg, Mass spectrum (+EI, [M+H]+) m/z 450. 1HNMR (500 MHz, DMSO-d6): δ14.16 (d, 1H, J=3.78 Hz), 9.97-10.10 (m*, 1H), 8.70-8.76 (m, 1H), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.26-8.28 (m, 1H), 8.02-8.04 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.63 (m, 3H), 7.27-7.37 (s* and s*, 1H), 7.08-7.20 (dd* and m*, 1H, J=9.03 Hz and 2.08 Hz), 4.59-4.80 (m*, 1H), 3.50-3.53 (m, 1H), 3.31-3.34 (m, 1H), 2.97-3.19 (m, 4H), 2.08-2.15 (m, 2H), 1.96-2.00 (m, 1H), 1.80-1.90 (m, 1H), 1.63-1.72 (m, 2H), 0.86-0.91 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: CO[C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].[C:14](#[N:16])[CH3:15].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]([CH3:11])([CH3:12])[C:3](=[O:13])[CH2:15][C:14]#[N:16]
Reactant: COCCOCC(C)(C)C(=O)OC
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCOCC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A solution of 3-(2-methoxy-ethoxy)-2,2-dimethyl-propionic acid methyl ester (3.08 g, 16.21 mmol) and acetonitrile (1.19 mL, 22.69 mmol) in toluene (6 mL) is added dropwise to the refluxing suspension of 60% sodium hydride in mineral oil (907.6 mg, 22.69 mmol) in toluene (18 mL). After the addition, the reaction mixture is stirred at reflux for 3 h. After this time, the reaction mixture is cooled to room temperature and the aqueous layer is neutralized to pH˜7 by adding 1M aqueous HCl solution. The aqueous layer is extracted with ethyl acetate 3 times. The organic layers are combined, washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield the title compound. Yield: 94.2%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (6H, s), 3.38 (3H, s), 3.47 (2H, s), 3.50-3.55 (2H, m), 3.57-3.62 (2H, m), 3.80 (2H, s).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH3:7][C:8]([CH3:15])([CH3:14])[C:9](=O)[C:10](O)=[O:11]>O>[C:8]([C:9]1[C:10](=[O:11])[N:2]([NH2:1])[C:3]([SH:4])=[N:5][N:6]=1)([CH3:15])([CH3:14])[CH3:7]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(=O)C(=O)O
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
Analogously to instructions given by A. Dornow and others (Chem. Brichte 97 (1964), page 2173-2178), 53 g (0.5 mole) of thiocarbohydrazide are dissolved in 500 ml of boiling water and 65 g (0.5 mole) of trimethylpyruvic acid are added slowly. A colorless precipitate is deposited, which is filtered off, washed with water and dried in vacuo at 50° C. 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5(4H)-one is obtained from this reaction in almost quantitative yield.
Reaction SMILES: S(Cl)([O:4][CH2:5][Cl:6])(=O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13](O)=[O:14].C(=O)([O-])O.[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[CH3:22][O:21][C:17]1[CH:16]=[C:12]([CH:11]=[C:10]([O:9][CH3:8])[C:18]=1[O:19][CH3:20])[C:13]([O:4][CH2:5][Cl:6])=[O:14]
Reactant: O=S(=O)(Cl)OCCl
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)OCCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
19 g of chloromethyl chlorosulphate in 30 ml of methylene chloride are introduced dropwise at room temperature into a stirred mixture of 21.1 g of 3,4,5-trimethoxybenzoic acid, 33.6 g of sodium hydrogen carbonate and 3.4 g of tetrabutylammonium hydrogen sulphate in 600 ml of methylene chloride-water (1:1). In order to complete the reaction, the mixture is stirred at room temperature for a further 2 hours, the two phases are then separated, the aqueous phase is washed with 100 ml of methylene chloride and the combined organic phases are dried over sodium sulphate. The solvent is removed in a vacuum and the residue is chromatographed over 450 g of silica gel with methylene chloride. Fractions containing the product are evaporated and the residue is crystallized from methylene chloride-petroleum ether. 10.5 g of chloromethyl 3,4,5-trimethoxybenzoate are obtained as colourless needles with a melting point of 85°-86°. RF (silica gel/methylene chloride): 0.45.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=[S:23])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(C#N)c3)cc21

Procedure:
Prepared by heating under reflux overnight a stirred mixture of 3-(4,4-dimethyl-2-oxo-1,2,3,4,-tetrahydroquinolin-6-yl)benzonitrile and an equal weight of phosphorus pentasulfide in pyridine and workup as in the previous example gave a yellow solid: mp 220-223° C. dec. 1H-NMR (DMSO-d6) δ 12.35 (s, 1H), 8.21 (s, 1H), 8.10 (d, 1H, J=6.0 Hz), 7.80 (d, 1H, J=7.9 Hz), 7.72 (s, 1H), 7.65 (m, 2H), 7.21 (d, 1H, J=8.4 Hz), 2.85 (s, 2H), 1.27 (s, 6H); MS (APCI(−)) m/z 291 [M−H]− Anal. Calc. For C18H16N2S 3H2O: C, 62.40, H, 6.40, N, 8.09. Found: C, 62.12, H, 4.88, N, 7.77.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]3Cl)[CH2:3][CH2:2]1.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[Cl:32].Cl>CO>[Cl:32][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:25]=1[F:24])[NH:29][C:14]1[C:13]2[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1
Temperature: 17.5 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Methanol (1200 ml) and 6-(3-morpholino propoxy)-7-methoxy-4-chloro quinazoline (200 gm) were stirred for 15 minutes at 25-30° C., then a solution of 4-fluoro-3-chloroaniline in methanol (213 gm in 400 ml) was charged and refluxed for 6 hours. The reaction mass was cooled to 15-20° C., hydrochloric acid (40 ml) was added drop wise, and stirred at 5-10° C. for 30 minutes. The solid obtained was filtered and washed with chilled methanol (150 ml). The solid was dissolved in a mixture of toluene (30 volume) and methanol (5 volume), the reaction mass was concentrated to half the volume and cooled to 5-10° C. The solid obtained was filtered, washed with toluene (200 ml) and dried at 45-50° C. to yield the title compound (183 gm, 70% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29]1([CH:35]2[O:40][C@H:39]3[CH2:41][C@@H:42](O)[CH2:43][O:44][C@@H:38]3[CH2:37][O:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:20]([O:28][C@@H:42]1[CH2:43][O:44][C@H:38]2[C@@H:39]([O:40][CH:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:36][CH2:37]2)[CH2:41]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triphenylphosphine (560 mg, 2.134 mmol) and benzoic acid (261 mg, 2.134 mmol) under nitrogen in anhydrous THF (8.0 mL) was added (4aR,7R,8aS)-2-phenylhexahydro-pyrano[3,2-d][1,3]dioxin-7-ol (500 mg, 2.134 mmol), then DIAD (0.41 mL, 428 mg, 2.116 mmol) dropwise over 10 minutes. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The resultant oil was dissolved in DCM, then loaded directly onto a Biotage™ 50 g (2×25 g in series) silica gel cartridge and eluted with 0-100% EtOAc in 1:1 Hexane/DCM over 25 column volumes. The product fractions were combined and concentrated under reduced pressure to provide the desired product as a white solid. LC-MS: calculated for C20H20O5 340.13, observed m/e: 341.13 (M+H)+ (Rt 2.21/4 min).