Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.CCN(C(C)C)C(C)C.[CH:58]1([S:61](Cl)(=[O:63])=[O:62])[CH2:60][CH2:59]1>ClCCl>[CH:58]1([S:61]([N:46]2[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:48][CH2:47]2)(=[O:63])=[O:62])[CH2:60][CH2:59]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (26 mg, 0.040 mmol) and Hunig's Base (0.035 mL, 0.198 mmol) in dichloromethane (1 mL) was added a solution of cyclopropanesulfonyl chloride (11.14 mg, 0.079 mmol) in dichloromethane (1 mL) at room temperature. The reaction mixture was stirred for 2 hours at 20° C. or LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was diluted with distilled water (4 mL), extracted with dichloromethane (3×4 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow solid (30 mg, 100%). LCMS: m/e 760.61 (M+H)+, 2.40 min (method 11).
Reaction SMILES: Cl.[CH2:2]([CH:4]([C:7]1[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[C:9]([O:16][CH3:17])[CH:8]=1)[CH2:5][CH3:6])[CH3:3].[OH:18][C:19]1[C:28]([CH2:29][CH2:30][CH3:31])=[CH:27][C:22]([C:23]([NH:25]O)=[NH:24])=[CH:21][C:20]=1[CH3:32]>>[CH2:5]([CH:4]([C:7]1[N:12]=[C:11]([C:13]2[O:15][N:25]=[C:23]([C:22]3[CH:27]=[C:28]([CH2:29][CH2:30][CH3:31])[C:19]([OH:18])=[C:20]([CH3:32])[CH:21]=3)[N:24]=2)[CH:10]=[C:9]([O:16][CH3:17])[CH:8]=1)[CH2:2][CH3:3])[CH3:6]
Reactant: CCCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCC(CC)c1cc(OC)cc(C(=O)O)n1
Agent: Cl
Product: CCCc1cc(-c2noc(-c3cc(OC)cc(C(CC)CC)n3)n2)cc(C)c1O
Yield: 3.1 %

Procedure:
The title compound (3 mg) is prepared by coupling and cyclizing 6-(1-ethyl-propyl)-4-methoxy-pyridine-2-carboxylic acid hydrochloride (64 mg, 246 μmol) and 4,N-dihydroxy-3-methyl-5-propyl-benzamidine (54 mg, 259 μmol) as described in Example 1; LC-MS**: tR=0.88 min, [M+H]+=396.29.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1.[CH2:12]([OH:15])[CH2:13][CH3:14]>>[Br:2][C:3]1[CH:8]=[C:7]([O:15][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccnc(Br)c1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1ccnc(Br)c1
Temperature: 95 °C
Yield: 58 %

Procedure:
To a solution of sodium (480 mg, 21 mmol) dissolved in 1-propanol (45 mL), was added 2-bromo-4-nitropyridine [(3.2 g, 19.2 mmol), J. Med. Chem. 46(7), 1273-1276; 2003] and the mixture was heated at 95° C. for 2 hours. The solvent was then evaporated under reduced pressure and the residue was suspended in chloroform and filtered. The filtrate was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give an oily residue. The residue was distilled and title product was obtained during a temperature range of 145-150° C., as a solid in 58% yield, 2.67 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=O.[C:12](#[N:15])[CH:13]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[CH:13][C:12]#[N:15]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1ccc(C=CC#N)cc1C
Yield: 31.8 %

Procedure:
0.448 g (2 millimols) of palladium acetate, 33.7 g (0.2 mol) of 3,4-dimethylbenzoyl chloride, 13.25 g (0.25 mol) of acrylonitrile and 37.06 g (0.2 mol) of tri-n-butylamine in 200 ml of p-xylene are stirred for 1.5 hours at 120° C. The mixture is then extracted by shaking with 200 ml of 2 N HCl, 200 ml of 2 N NaOH and 100 ml of water, after which it is dried for 15 minutes with 20 g of magnesium sulfate. The crude product is chromatographed on silica gel in methylene chloride, and is recrystallised from n-hexane. 10.0 g (32% of theory) of 3,4-dimethylcinnamonitrile are obtained as pale yellow crystals, melting point 93.9° C. Analysis for C11H11N: calculated C 84.04%, H 7.05%, N 8.91%; found C 83.65%, H 6.87%, N 9.03%.
Reaction SMILES: [CH:1]1([C:4]2[C:12](I)=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.CCOCC>[CH:1]1([C:4]2[C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCc1cc(C2CC2)c(I)cc1C(=O)O
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 102 %

Procedure:
To a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid (compound 226.5, 500 mg, 1.58 mmol, 1.00 equiv) in THF/Et2O (10/10 mL) under nitrogen at −78° C. was added dropwise n-butyllithium (2.5 M, 1.88 mL, 3.00 equiv) over 3 min. After stirring for 10 min at −78° C., methyl chloroformate (230 mg, 2.43 mmol, 1.50 equiv) was added dropwise at −78° C. The resulting solution was stirred for 40 min at −78° C., then warmed slowly to −35° C. The reaction was carefully quenched with 2 mL of water. The pH was adjusted to ˜4-5 with hydrogen chloride (aq., 1 M). The resulting mixture was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 400 mg the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>>[CH3:19][C:18]1[N:1]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=2)[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NCCCc1ccc(C(N)=O)s1
Product: Cc1ccc(C)n1CCCc1ccc(C(N)=O)s1

Procedure:
5-(3-Aminopropyl)-2-thiophenecarboxamide is reacted with acetonylacetone to give 5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide, m.p. 144°-146° C. (see J. Chem. Soc. Chem. Commun. 800 [1982]). This is alkylated with n-butyl bromide to give N-butyl-5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide (see Synthesis 266 [1976]). The latter is cleaved with hydroxylamine hydrochloride to give 5-(3-aminopropyl)-N-butyl-2-thiophenecarboxamide.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:9]([SH:13])[CH:10]([SH:12])[CH3:11]>>[CH3:11][CH:10]1[S:12][C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[S:13][CH2:9]1
Reactant: CC(S)CS
Reactant: O=C1CCCCC1Cl
Product: CC1CSC2=C(CCCC2)S1
Yield: 66 %

Procedure:
The procedure of Example 1(a) is followed using 2-chloro-cyclohexanone and 1,2-propanedithiol to give 5,6,7,8-tetrahydro-2-methyl-1,4-benzodithian as a greenish oil, bp 127°-130°/2.3 mm, Yield 66%. NMR, 1.36 (3d), 1.4-1.88 (4m), 1.88-2.3 (4m), 2.6-3.7 (3m). IR, 2920, 1615, 1410, 1325, 1250, 1120, 855, 715.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.O>C1COCC1>[C:21]1([CH3:26])[C:20]([NH:19][CH:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:16])[C:9](=[O:17])[C:8]3[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccccc1N
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1NC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of compound (6) (2.0 mmol) in dry THF (20 ml) was added dropwise a solution of o-toluidine (10 ml) in dry THF (10 ml) under N2. The reaction mixture was stirred at room temperature for 24 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].C([Li])CCC.[CH3:13][C:14](=[O:17])[CH2:15][CH3:16]>O1CCCC1>[CH3:13][C:14]([OH:17])([C:4]#[C:3][C:2]([CH3:1])([OH:7])[CH2:5][CH3:6])[CH2:15][CH3:16]
Reactant: C#CC(C)(O)CC
Reactant: CCC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C)(O)C#CC(C)(O)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of 3-methyl-1-pentyn-3-ol (30 g, 0.3 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and n-butyl lithium (1.6 molar solution in hexanes, 383 ml, 0.611 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of 2-butanone (41 ml, 0.458 mol) in tetrahydrofuran (50 ml) is added. The reaction mixture is stirred at −78° C. for one hour, allowed to come to ambient temperature and stirred for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The aqueous phase is extracted with dichloromethane (3×200 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 3,6-dimethyloct-4-yne-3,6-diol (27 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[N:8]2[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)Nc2cc(Br)ccc21
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(C)(C)c2ccc(Br)cc21
Temperature: 80 °C

Procedure:
To a suspension of 6-bromo-3,3-dimethylindolin-2-one (example 14a, 1.68 g, 7.00 mmol) in DMF (30 ml) were added 2-bromopropane (2.15 g, 1.64 ml, 17.5 mmol) and cesium carbonate (5.02 g, 15.4 mmol). The reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was treated with 1 M HCl and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as orange solid (2.00 g, 70% purity) and was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([O:21]CC)=[O:20])=[C:11]2C)[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=[O:20])=[CH:11]2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(c1ccc(Cl)cc1)n1cc(C(=O)O)c2ccccc21
Yield: 109.4 %

Procedure:
To a mixture of ethyl 1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-indole-3-carboxylate (210 mg, 0.61 mmol) in MeOH/H2O (6 mL/2 mL) was added KOH (340 mg, 6.1 mmol) at room temperature. The reaction was refluxed overnight. Then the mixture was adjusted to Ph=4 with 1 N HCl and extracted with EtOAc (3×). The combined organic extract were combined and concentrated in vacuo to afford the title compound as a yellow solid (200 mg, yield 105%) which was used without further purification.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[C:14]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44]([NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8, Example 1, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride and 1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 636 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]2=[N:15][C:14]=1[CH3:28].[CH2:29]1COCC1.[Li]C(C)(C)C.CI>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:29])[N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:16]2=[N:15][C:14]=1[CH3:28]
Reactant: C1CCOC1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Agent: [Li]C(C)(C)C
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nc(C)nn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 42 %

Procedure:
To a −78° C. solution of 3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.72 mmol) and THF (5 mL) is added 1.7 M tert-BuLi (0.47 mL, 0.80 mmol). After 15 minutes MeI (0.052 mL, 0.83 mmol) is added and the solution warmed to ambient temperature. The solution is diluted with EtOAc (40 mL), washed with brine (40 mL), dried over MgSO4, filtered and concentrated. The solution is recrystallized from acetone:hexane furnish the title compound (0.13 g, 0.30 mmol, 42%). 1H NMR (CDCl3) δ0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.36 (s, 3H), 2.51 (s, 6H), 3.27-3.39 (m, 1H), 3.40 (s, 3H), 6.72 (s, 1H), 8.02 (s, 1H). LC/MS (m/z): calcd. for C21H25ClN6S (M+H)+: 429.2; found: 429.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[CH:23]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1ccc(-c2cccs2)cc1
Product: CCOc1ccc(-c2ccc(Cc3cc(Br)ccc3F)s2)cc1

Procedure:
2-(4-Ethoxyphenyl)thiophene obtained in Reference Example 68—(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 391/393 (M+H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(OCC)=O>CCOCC>[Cl:7][CH:8]([CH:2]=[O:4])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC=O
Product: O=CC(Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To potassium tert-butoxide (141 mL, 141 mmol) at 0° C. was added dropwise a solution of benzyl 2-chloroacetate (26.8 g, 141 mmol) and ethyl formate (11.6 mL, 141 mmol) in Et2O (45 mL). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was filtered and washed with cold ether (100 mL). The potassium salt was dissolved in H2O (50 mL) and the solution was acidified with concentrated HCl to pH=4 in a cold bath. The solution was extracted with ether and the organic phase was dried (MgSO4) and concentrated to give the crude product. A lower boiling point impurity was removed by vacuum distillation (90° C., 5 mm Hg) and the residue was taken directly to the next step.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>ClC1C=CC=CC=1Cl>[Cl:3][C:2]1[N:4]=[C:5]([C:22]2[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[N:7]=[C:8]([C:22]2[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[N:1]=1
Reactant: CC(C)(C)c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride and 3 eq of aluminum chloride in o-dichlorobenzene at ice bath temperature was added concentrated HCl (13 wt % based on cyanuric chloride). After 10 minutes, 1.95 eq of tert-butylbenzene was added and the reaction was stirred at ice bath temperature for 10 minutes. The cooling bath was removed, the reaction mixture was allowed to warm to room temperature, and stirred. After 2 h, HPLC analysis indicated 62% cyanuric chloride conversion to 2-chloro-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine as the major product (>78%). The reaction mixture was stirred at room temperature for an additional 24 h. HPLC analysis showed 83% cyanuric chloride conversion to 2-chloro-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine as the major product (>72%), with the isomer.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28](O)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([C:44]([F:47])([F:46])[F:45])[CH2:41][C@H:40]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:51]([O:50][C:49]([NH:48][C@H:40]1[CH2:41][C@@H:42]([C:44]([F:47])([F:46])[F:45])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:29])[CH2:39]1)=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
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)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.015 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and aqueous phase was extracted with EtOAc. The organic phases were combined and concentrated under vacuum. The residue was purified by flash chromatography on 20 g silica gel column, eluting with 0-30% MeOH in EtOAc, to yield an amide intermediate, benzyl {2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-morpholin-4-ylquinolin-3-yl}carbamate.
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl.[C:17](=[NH:22])(OCC)[CH3:18].C(N(CC)CC)C>ClCCl>[CH2:12]([O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[N:22]=[C:17]([CH3:18])[O:15][N:14]=2)[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@H](c2noc(C)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (1.85 g, 7.92 mmol) and ethyl acetimidate hydrochloride (1.96 g, 15.8 mmol) in dichloromethane (40 ml) was added triethylamine (2.2 ml, 16 mmol) at 0-5° C. The cooling bath was removed 15 minutes after completed addition, and stirring for 18 h at room temperature was followed by heating at reflux for 4 h. The reaction mixture was washed with one 50-ml portion of 1 M aqueous hydrochloric acid solution. The aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/tert-butyl methyl ether as eluent gave the title compound (1.05 g, 56%) as colorless oil. MS m/e: 239 ([M+H]+)
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1.[C:26](O)(=[O:29])[CH2:27][OH:28]>>[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:27](=[O:28])[CH2:26][OH:29])[CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: O=C(O)CO
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (300 mg) was reacted with glycolic acid via General Procedure B to give 306 mg of 1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone.