Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid morpholine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1.ClC1C=C(Cl)C=CC=1C1[C:38]([C:39]2[NH:40][CH:41]=[CH:42][N:43]=2)=[CH:37][N:36]=[C:35]([NH:44][CH2:45][CH2:46][NH:47]C2C=CC([N+]([O-])=O)=CN=2)[N:34]=1>>[NH:40]1[CH:41]=[CH:42][N:43]=[C:39]1[C:38]1[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:34][C:35]([NH:44][CH2:45][CH2:46][NH:47][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[N:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: FC(F)(F)c1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1

Procedure:
{5-imidazol-2-yl-4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}(2-{[5-(trifluoro-methyl)(2-pyridyl)]amino}ethyl)amine was prepared from 4-(trifluoromethyl)benzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:10][CH3:11])=[N:6][O:7][C:8]=1[CH3:9])(=O)[CH3:2].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[C:12]1([NH:18][N:19]=[C:1]([C:4]2[C:5]([CH2:10][CH3:11])=[N:6][O:7][C:8]=2[CH3:9])[CH3:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: CCc1noc(C)c1C(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: CCc1noc(C)c1C(C)=NNc1ccccc1

Procedure:
A mixture of 61.1 g. (0.4 mole) of 4-acetyl-3-ethyl-5-methyl-isoxazole, 39.4 ml. (0.4 mole) of phenyl hydrazine and 500 mg. toluenesulfonic acid in 400 ml. ethanol is stirred at room temperature for 48 hours. The resulting solid is filtered and washed with cold ether to give 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone phenyl hydrazone; m.p. 72° to 75° C.
Reaction SMILES: C[OH:2].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC(Cl)=O.C(N(CC)CC)C.[CH2:24]([O:26][CH2:27][CH3:28])C>>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:28][C:27]([O:26][CH3:24])=[O:2]
Reactant: CCOCC
Reactant: CO
Reactant: O=C(Cl)CCCCCCCCCCBr
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCCCBr
Temperature: 25 °C

Procedure:
With cooling and stirring, 4.0 ml (0.099 mole) of methanol was added to 25.6 grams (0.090 mole) of 11-bromoundecanoic acid chloride. Triethylamine, 13.8 ml (0.099 mole) was then added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 16 hours. The reaction mixture was diluted with diethyl ether and was washed in turn with water, an aqueous solution saturated with sodium bicarbonate, water, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 23.9 grams of methyl 11-bromoundecanoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:18]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1)[C:25](=[O:26])/[CH:24]=[CH:23]/[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: CNCCc1cc(OC)c(OC)c(OC)c1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CCN(C)C(=O)/C=C/c2cccnc2)cc(OC)c1OC
Yield: 93.5 %

Procedure:
N-Methyl-3,4,5-trimethoxyphenethylamine (1.60 g, 7.11 mmol) and trans-3-(3-pyridyl)acrylic acid (1.17 g) were dissolved in dimethylformamide (8 ml), and diethylphosphoric cyanide (1.3 ml) and triethylamine (2.2 ml) were sequentially added under ice-cooling and stirring and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane, washed with water and dried over potassium carbonate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1) to yield amorphous (E)-N-methyl-3-(3-pyridyl)-N-(3,4,5-trimethoxyphenethyl)-2-propenoic acid amide (2.37 g, 94%). Then, hydrogen chloride-methanol was added to the product (1.80 g) to produce its hydrochloride, which was recrystallized in a mixed solvent of ethyl acetate-methanol to yield the titled compound (1.59 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:31])([F:30])[CH2:28]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:28][C:27]([F:31])([F:30])[F:26]
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 100 °C
Yield: 569 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57 mmol) and K2CO3 (1.58 g, 0.011 mol) in dry DMF (20 mL), slowly added trifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at room temperature. Upon completion of the addition, the reaction mixture was slowly heated to 100° C. for 4 h. Upon completion, the reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic layer were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.4 g, 60% yield). 1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[Cl:13][C:14]1[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[CH:17]=[CH:16][C:15]=1[NH2:24].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:13][C:14]1[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[CH:17]=[CH:16][C:15]=1[NH:24][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)Cc3ccc(Cl)cc3Cl)ccc2s1
Yield: 34.6 %

Procedure:
Reaction of 2,4-dichlorophenylacetic acid (163 mg, 0.79 mmol) in thionyl chloride (2 mL) then with 4-chloro-2-methyl-benzothiazol-5-ylamine (52 mg, 0.26 mmol) in presence of triethylamine (0.5 mL) in THF (3 mL) according to method B gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(2,4-dichloro-phenyl)-acetamide (33 mg, 0.09 mmol, 35% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C@@H:17]4[CH2:21][OH:22])=[O:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)(O)[O-].[Na+].O.C(#N)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:22][CH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)[CH:24]=[CH:23][C:5]=3[C:6]=2[N:7]=1)=[O:15]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(c1nc2c(s1)CCOc1cc(Br)ccc1-2)N1CCC[C@@H]1CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H]1CO
Temperature: 25 °C
Yield: 16.7 %

Procedure:
(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone (0.297 g, 0.726 mmol), 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (0.211 g, 1.09 mmol), 2 M Sodium bicarbonate in water (1 mL, 2.0 mmol) and acetonitrile (2 mL, 40 mmol) were combined in a microwave vial and thoroughly purged with nitrogen. Added Tetrakis(triphenylphosphine)palladium(0) (0.0838 g, 0.0726 mmol) and heated on the Emrys microwave at 150° C. for 10 minutes. Cooled to room temperature, diluted with ethyl acetate, washed with brine and concentrated the organic layer in vacuo. Purified by HPLC to give 101 (48 mg, 17% yield, M+1 397.1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: CC(C)S(=O)(=O)c1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CC(C)S(=O)(=O)c1ncccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared as described in step D of Example 803 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 3-bromo-2-(isopropylsulfonyl)pyridine. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.7, 1.7, 1H), 8.57 (d, J=1.4, 2H), 7.80 (dd, J=7.8, 1.6, 1H), 7.59 (dd, J=7.8, 4.6, 1H), 7.46 (m, 1H), 7.39 (dd, J=7.9, 1.8, 1H), 7.32 (dd, J=11.1, 1.7, 1H), 5.17 (s, 2H), 4.26 (hept, J=6.9, 1H), 1.32 (d, J=6.9, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1C=CC=CC=1.N1CCCCC1>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=Cc1cc2ccccc2s1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cc2ccccc2s1

Procedure:
To a mixture of 1-benzothiophene-2-carbaldehyde, malonic acid (1.5 equiv) and pyridine (2.5 equiv) was added piperidine (0.1 equiv). The mixture was heated to reflux for 6 h, cooled and poured into H2O and filtered. Air drying over night gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 62%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[C:8]([CH3:14])[C:6]=2[N:7]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([S:22]([CH3:21])(=[O:24])=[O:23])[CH3:13])=[C:8]([CH3:14])[C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1sc2c(N3CCOCC3)nc(Cl)nc2c1C
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: Cc1c(CN(C)S(C)(=O)=O)sc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc12
Yield: 29 %

Procedure:
1-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 56 from Example 11b was reacted with methanesulfonylchloride (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 31.0 mg of 391 after RP-HPLC purification (29% yield). MS (Q1) 473.2 (M)+
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].N1CCCCC1.[C:13]([O:18][CH3:19])(=[O:17])/[CH:14]=[CH:15]/[CH3:16]>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH:15]([CH3:16])[CH2:14][C:13]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CS
Reactant: C/C=C/C(=O)OC
Solvent: C1CCNCC1
Product: COC(=O)CSC(C)CC(=O)OC
Reaction time: 15 h
Yield: 88.6 %

Procedure:
To a mixture of methyl thioglycolate (45 mL, 503.2 mmol) and piperidine (0.8 mL) at 0° C. was slowly added methyl crotonate (67 mL, 631.7 mmol). Additional piperidine (0.8 mL) was added in two portions after ten and twenty minutes. After stirring for 15 hours, the mixture was purified by vacuum distillation. The fraction was collected at 110-112° C. to give methyl 3-(2-methoxy-2-oxoethylthio)butanoate (92 g, 89%). 1H NMR (CDCl3, 400 MHz) δ 3.75 (s, 3H), 3.70 (s, 3H), 3.38-3.44 (m, 3H), 2.71-2.46 (m, 2H), 1.36 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].[NH2:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:34]=[C:33]([CH2:35][CH3:36])[C:23]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:37]>C(OCC)C.[OH-].[Na+]>[C:25]([NH:24][C:23]1[C:33]([CH2:35][CH3:36])=[CH:34][N:19]([C@@H:17]2[O:18][C@H:14]([CH2:13][NH:12][C:9](=[O:10])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C@@H:15]([OH:37])[CH2:16]2)[C:20](=[O:21])[N:22]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)nc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3Br)O2)c(=O)nc1NC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
A solution of 210 mg of (2-bromophenyl)acetyl chloride in 3 ml of diethyl ether was added to a solution of 324 mg of 5'-amino-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in 4.9 ml of 0.18M sodium hydroxide solution and the mixture was shaken vigorously for 10 minutes. The solid was collected by filtration, washed with 2 ml of water and 1 ml of diethyl ether and recrystallized from 15 ml of ethanol to give 100 mg of 4-N-benzoyl-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethylcytidine in the form of a white solid which was processed further without purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CSC.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:30])=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=4)[CH:19]=3)[C:14](=[O:31])[C:13]([C:32]([O:34]CC)=[O:33])=[C:12]2[N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:10][CH2:9]1>ClCCCl.C(Cl)(Cl)Cl>[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:30])=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=4)[CH:19]=3)[C:14](=[O:31])[C:13]([C:32]([OH:34])=[O:33])=[C:12]2[N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1c(N2CCOCC2)n(C2CC2)c2cc(Cc3nc(C(C)C)cs3)c(F)cc2c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CSC
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)c1csc(Cc2cc3c(cc2F)c(=O)c(C(=O)O)c(N2CCOCC2)n3C2CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
A solution of aluminum chloride (266 mg, 2.00 mmol) in 1,2-dichloroethane (4 ml) was added with dimethyl sulfide (0.293 ml, 4.00 mmol) and stirred at 0° C. for 30 minutes. Then, the reaction mixture was added with ethyl 1-cyclopropyl-6-fluoro-7-[(4-isopropyl-1,3-thiazol-2-yl)methyl]-2-morpholino-4-oxo-1,4-dihydro-3-quinolinecar boxylate (51.5 mg, 0.0999 mmol) and refluxed overnight by heating. The reaction mixture was left stand for cooling, diluted with chloroform, washed with 1 N hydrochloric acid, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by preparative TLC (chloroform:methanol=10:1) to obtain the title compound (1.3 mg, 3%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11](=[O:13])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[O:13]=[C:11]1[NH:10][CH:9]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:3][CH2:4]2)[S:12]1
Reactant: O=C1CCC(c2c[nH]c(=O)s2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3c[nH]c(=O)s3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-(4-oxo-cyclohexyl)-3H-thiazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH:14][C:15](=O)[CH2:16][Cl:17])[CH:7]=1)[CH2:2][CH3:3]>C(O)(=O)C>[CH2:1]([N:4]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5]([C:6]1[CH:11]=[CH:10][C:9]2[N:12]([CH3:13])[C:15]([CH2:16][Cl:17])=[N:14][C:8]=2[CH:7]=1)=[O:19])[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(NC(=O)CCl)c1
Solvent: CC(=O)O
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CCl)n2C

Procedure:
1.6 g (4.3 mmol) of 4-methylamino-3-chloracetamidobenzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide were heated to 100° C. in 25 mL of acetic acid for 30 minutes. Then the solvent was distilled off, the crude product was taken up in 40 mL methylene chloride/ethanol (9:1) and washed with 20 mL saturated sodium hydrogen carbonate solution. The organic phase was dried with sodium sulfate and evaporated down. Yield: 1.5 g (100% of theory) of brown oil; Rf value: 0.63 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#N.S(=O)(=O)(O)[OH:13].[OH2:17]>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]([OH:13])=[O:17]
Reactant: Cc1ccc(CC#N)c(C)c1
Reactant: O=S(=O)(O)O
Reactant: O
Product: Cc1ccc(CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-Dimethylbenzylcyanide (70 g, 0.48 mol) was mixed with water (134 ml) and concentrated sulfuric acid (106 ml, 1.98 mol) was added slowly. The reaction was heated to reflux for 3 hours, then cooled to room temperature over 18 hours. The mixture was poured onto crushed ice (500 ml), stirred for one hour and the resulting precipitate was isolated by filtration. After washing with water the solid was dissolved in 1.2M sodium hydroxide solution (500 ml), extracted with dichloromethane (2×250 ml) and the aqueous phase was treated with decolourising carbon (2 g) at reflux for 10 min and filtered hot through hyflo supercel. The filtrate was then acidified with concentrated hydrochloric acid and the resulting precipitate was isolated by filtration, washed with water and dried under vacuum to give 2,4-dimethyl-phenyl-acetic acid (52.6 g) as a white solid. 1H NMR (250 MHz, CD3OD/D2O): δ=6.88-7.03 (3H, m), 3.48-3.68 (2H, s), 2.23 (6H, s), ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3cnc(N)nc3)ccn2)cn1
Temperature: 85 °C
Yield: 55.8 %

Procedure:
5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine (676 mg, 3.04 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (758 mg, 3.64 mmol), potassium carbonate (1.259 g, 9.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (175 mg, 0.152 mmol) were combined in dioxane (12 mL) and water (3 mL). The mixture was degassed with argon, sealed and warmed to 85° C. overnight. The mixture was diluted with EtOAc (75 mL) and water (40 mL) and was filtered to collect an off-white solid. The organic phase was separated, washed with brine (40 mL) and evaporated at reduced pressure to give additional off-white solid. The two crops of solids were combined and triturated with EtOAc (15 mL) with sonication. The solid was collected by filtration, washed with EtOAc (2×5 mL) and dried under vacuum to provide 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-amine (455 mg, 55%). 1H NMR (DMSO-d6): δ 8.34 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 8.22 (s, 2 H), 7.96 (s, 1 H), 7.19 (d, J=2.4 Hz, 1 H), 6.77 (s, 2 H), 6.67 (dd, J=5.7, 2.5 Hz, 1 H), 3.84 (s, 3 H); MS (ESI) m/z: 269.1 (M+H+).