Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[N:15]([CH3:20])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.C(Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([N:15]1[C:14](=[O:21])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:22])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH2:19][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(C)c2=O)cn1
Reactant: BrCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(Cc3ccccc3)n(Cc3ccccc3)c2=O)cn1
Yield: 69 %

Procedure:
Prepared as in Example 10-65 from 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2-dimethyl-1,2,4-triazolidine-3,5-dione (example 10-69) and benzyl bromide. Yield: 69%. 1H NMR (CDCl3, 400 MHz): δ2.14 (s, 3H), 2.36 (s, 3H), 4.65 (s, 4H), 4.99 (s, 2H), 7.06-7.08 (m, 4H), 7.19-7.25 (m, 6H), 7.86 (s, 1H), 8.02 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.8 μM.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.3 %

Procedure:
The ethyl 3-(4-nitrophenyl)acrylate (512.8 mg) obtained in the above step (a) was dissolved in dioxane (5.1 ml), and the solution was added with 5 N sodium hydroxide (2.78 ml) and stirred at room temperature for 3.5 hours. Separation and extraction with diethyl ether was made to remove impurities, and then: 5 N hydrochloric acid was added to the aqueous layer to reduce the pH to 2. The precipitated crystals were collected by filtration to obtain 3-(4-nitrophenyl)acrylic acid (270.1 mg, 60.3%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH2:26][C:27]#[N:28])[CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:29]>>[C:27]([C:26]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:8]([CH3:7])[C:9](=[O:29])[CH:10]=[CH:11]4)[CH:21]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[N:28]
Reactant: C1CCOCC1
Reactant: Cn1c(=O)ccc2cc(COc3cccc(CC#N)c3)ccc21
Product: Cn1c(=O)ccc2cc(COc3cccc(C4(C#N)CCOCC4)c3)ccc21
Yield: 61 %

Procedure:
Using the procedure described in the third paragraph of the portion of Example 2 which is concerned with the preparation of 4-ethoxycarbonyl-4-(3-hydroxypheny])tetrahydropyran, 3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenylacetonitrile was reacted with bis-2-chloroethyl ether to give 4-cyano-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 61% yield, m.p. 149°-150° C. (recrystallised from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:38][C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][N:29]=[C:28]2[Cl:27])=[CH:33][CH:34]=1
Reactant: Cc1ccc2ccnc(Cl)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1nccc2ccc(CBr)cc12
Temperature: 25 °C
Yield: 97 %

Procedure:
N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide (0.39 g, 1.13 mmol) are added to a solution of 1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride (70 mL). The resulting mixture is heated to reflux for 6 hours then cooled to room temperature and diluted with methylene chloride. The organic layer is washed with 1N NaOH and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes to give the product (1.4 g, 5.46 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2C(OC(C)(C)C)=O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>>[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([C:16]([S:26]([CH3:28])=[O:27])=[CH:15][N:14]2[C:11]2[N:12]=[CH:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][N:10]=2)=[CH:18][CH:19]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CC4CC3CN4)ccc12

Procedure:
Prepared from 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid and tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in two steps comprising a T3P coupling and a TFA-catalyzed removal of the Boc protecting group. Light yellow solid.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:45]([NH2:47])=[O:46])[CH2:24][S:25][C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C>CN(C)C=O>[NH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:45]([NH2:47])=[O:46])[CH2:24][S:25][C:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:21]
Reactant: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O

Procedure:
1.53 g (2.38 mmol) of the compound from example 17A was dissolved in 18 ml dimethyl formamide and 0.47 ml (4.79 mmol) DIEA was added. After one hour reaction time, the raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 416 mg (0.97 mmol, 40% of theory) of the desired product.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[Cl-].[NH4+]>C1COCC1>[S:5]1[CH:6]=[C:2]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]1=2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1csc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
32.0 9 (150 mmol) of 3-bromo-benzo[b]thiophene are added dropwise at -78° C. to a solution of 150 mmol of n-butyllithium in 500 ml of anhydrous THF. The mixture is stirred at -78° C. for 1 h, 52.1 g (160 mmol) of tri-n-butyl-tin chloride are added and the mixture is allowed to warm to room temperature. For working-up, saturated ammonium chloride solution is added and the mixture is extracted with ether. After chromatography on silica gel using petroleum ether, 14.8 g (23 % of theory) of the title compound are obtained.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[O:32]=[C:33]([NH:42][C@H:43]([C:48]([NH:50][CH:51]([CH2:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1)[CH:52]([P:54]([CH2:58]C)([O:56][CH3:57])=[O:55])[OH:53])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[CH:61]1([CH2:60][C@H:51]([NH:50][C:48](=[O:49])[C@H:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:42][C:33](=[O:32])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:52]([P:54]([CH3:58])(=[O:55])[O:56][CH3:57])[OH:53])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: CCP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COP(C)(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 61.5 %

Procedure:
Hydroxybenzotriazole 85.7 mg, 0.56 mmol), diisopropylethylamine (90.6 μl, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (107.3 mg, 0.56 mmol) were sequentially added to a solution of the title D compound (114.2 mg, 0.4 mmol) and compound B from Example 17 (126.2 mg, 0.48 mmol) in 2 ml dimethylformamide at 0°. The reaction mixture was warmed and stirred at room temperature for 60 hours after which it was concentrated, then treated with 15 ml pH=4.01 buffer and extracted with ethyl acetate (3×25 ml). Drying and concentration gave 425 mg crude product which after flash chromatographic purification (20 g silica gel, 19:1 CHCl3 /MeOH) gave 146 mg (74%) of the title compound Isomer A which was characterized by MS, IR, 1H NMR and 13C NMR. After repeated chromatography and finally, crystallization from hexane/ethyl acetate, the title compound Isomer A (56 mg) was obtained, m.p. 165°-170° C. [α]D =-67.1° (c=0.66, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[OH-].[Na+].Cl.O>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cc3c(Cl)c(Cl)cnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
A suspension of Example 113C (0.35 g, 0.831 mmol) in methanol (9.2 mL) was treated with 2 N aqueous sodium hydroxide solution (2.08 mL, 4.15 mmol), and the reaction was heated to 70° C. for 10 minutes. The reaction was cooled to ambient temperature, and the pH was adjusted to pH ˜7 with 10% aqueous HCl solution. The neutralized mixture was treated with water (12 mL), and the resulting suspension was cooled to 0° C. and filtered. The solid was collected, washed with water, and dried in a vacuum oven at 60° C. to provide the title compound. MS ESI(+) m/z 267.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:8][CH:9]=1)=[O:4].C(Cl)(Cl)[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:8]([Cl:19])[CH:9]=1)=[O:4]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1ccc(OCCn2ccnc2)s1
Product: COC(=O)c1cc(Cl)c(OCCn2ccnc2)s1
Temperature: -40 °C

Procedure:
0,15 g of 5-[2-(1-imidazolyl)-1-ethoxy]-thiophene-2-carboxylic-acid methyl ester (formula I: R=H, R1 =CH3) were dissolved in 5 ml of absolute chloroform, cooled to -40° C. and 0,16 g (1,19 mol) of SO2Cl2 were dropped thereto such that the temperature did not exceed -35° C. After standing over night it was evaporated in vacuo, the residue was partioned between 2N HCl and ether, the aqueous phase was extracted several times with ether, neutralized with sodium hydrogen carbonate and extracted several times with methylene chloride. The combined methylene chloride phases were dried (sodium sulfate) and evaporated, the residue from the evaporation was separated by column chromatography (eluant: benzene/ethanol 9:1). Yield 73 mg (43%), melting point 97°-99° C. (benzene/ether), colorless crystals.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1cc(OC)c(C(=O)OC)cc1[N+](=O)[O-]
Yield: 29629.7 %

Procedure:
The title compound was prepared following the procedure described for Step-4 of Intermediate-1 using methyl 2-fluoro-4-(methylamino)-5-nitrobenzoate (12.00 g, 0.0562 mmol) and sodium methoxide (22.73 g, 0.4210 mmol), methanol to afford 4.00 g of the desired product. 1HNMR (DMSO-d6): δ 3.02 (d, J=4.5 Hz, 3H), 3.75 (s, 3H), 3.94 (s, 3H), 6.28 (s, 1H), 8.57 (s, 1H), 8.62 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][CH:8]=[C:7](O)[C:6]=2[CH:15]=1.[CH3:16][NH:17][CH3:18]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][CH:8]=[C:7]([N:17]([CH3:18])[CH3:16])[C:6]=2[CH:15]=1
Reactant: O=S1(=O)CCC=C(O)c2cc(Cl)ccc21
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C1=CCCS(=O)(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred suspension of 1.09 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1,1-dioxide in 20 ml of benzene the solution of 0.5 g of titanium tetrachloride in 10 ml of benzene is added dropwise while cooling with ice, and the mixture stirred for 1/2 hour at 0°. Thereupon the solution of 0.7 g of dimethylamine in 10 ml of benzene is added dropwise and the mixture allowed to warm up to room temperature. It is filtered, the filtrate evaporated, and the residue recrystallized from diethyl ether, to yield the 7-chloro-5-dimethylamino-2,3-dihydro-1-benzothiepin-1,1-dioxide melting at 93°-95°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:42][CH2:41][CH:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:23][CH2:24]2)=[O:18])[C:13]([N:46]2[CH2:47][CH2:48][CH:43]([CH:40]3[CH2:41][CH2:42][N:37]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:38][CH2:39]3)[CH2:44][CH2:45]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3ccc(CC)c(CC)c3)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and ethyl [4,4′]bipiperidinyl-1-yl-acetate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([N:23]4[CH2:24][CH2:25][CH:21]([N:20]([CH3:36])[CH3:19])[CH2:22]4)[S:27][C:28]=3[CH:34]=2)=[O:9])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4cccc(Cl)c4)cc3s2)C1
Yield: 49.2 %

Procedure:
Combine 3-chlorocinnamic acid (0.104 g, 0.572 mmol), CH2Cl2 (13 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.17 mL, 1.91 mmol) and stir the mixture for 2.5 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a mixture of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial for 1 h at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with 1.0 M NaOH (aqueous) (4×25 mL), dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue using silica gel chromatography (12 g column, 10-20% MeOH(CH2Cl2) to afford the title compound as a yellow solid (80 mg, 49%). mass spectrum (m/e): 427.2 [M+1], 425.2 [M−1]. 1H NMR (400 MHz, CDCl3 (spiked with CD3OD)): δ 8.28 (s, 1H), 7.61 (d, 1H, J=15.6 Hz), 7.47-7.43 (m, 2H), 7.32 (d, 1H, J=7.2 Hz), 7.30-7.23 (m, 2H), 7.19 (dd, 1H, J=8.8, 2.0 Hz), 6.57 (d, 1H, J=15.6 Hz), 3.78 (t, 1H, J=8.8 Hz), 3.68 (t, 1H, J=10.0 Hz), 3.50 (m, 1H), 3.36 (t, 1H, J=9.2 Hz), 2.88 (m, 1H), 2.29 (s, 6H), 2.23 (m, 1H), 1.97 (m, 1H).
Reaction SMILES: C([NH:8][CH2:9][C:10](O)=[O:11])(OC(C)(C)C)=O.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=1>C(Cl)Cl.CO>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([N:22]([C:10](=[O:11])[CH2:9][NH2:8])[CH3:23])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNc1ccc(C(=O)OC)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N(C)C(=O)CN)cc1

Procedure:
BOC-glycine and methyl-4-methylaminobenzoate according to 1.2., followed by BOC-cleavage 3.1. to give 4-(Aminoacetyl-methyl-amino)-benzoic acid methyl ester as an orange gum (Rf 0.1 CH2Cl2:MeOH 9:1), MS: 222 (MH+).
Reaction SMILES: C([C:9]1[CH2:20][N:12]2[C:13](=[O:19])[N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[N:10]=1)(=O)C1C=CC=CC=1.[H-].[Na+].I[CH2:24][CH3:25].O>CN(C)C=O>[CH2:24]([N:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]2=[N:10][CH:9]=[CH:20][N:12]2[C:13]1=[O:19])[CH3:25]
Reactant: COc1cc2n(c(=O)n1)CC(C(=O)c1ccccc1)=N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(OC)cc2nccn2c1=O
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A stirred solution of 11 g of 2-benzoyl-7-methoxyimi-dazo[1,2-c]pyrimidin-5-one in 33 ml of dry dimethylformamide was treated with 1.27 g of 80% of sodium hydride and was stirred for another hour. 8 g of iodoethane were added dropwise over 10 minutes and stirring was continued for two hours after which the mixture was poured into iced water. The mixture was filtered to obtain 2.3 g of 6-ethyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one as a yellow crystalline solid melting at 159°-60° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:18][C:19](=O)[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:22]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:21]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:19](=[O:18])[C:20]2[CH:21]=[C:22]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: NCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCc1ccccc1)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a flamed dried round bottom flask with 3-phenyl-1-propylamine (0.404 mL, 2.84 mmol) and THF (5 mL) cooled to −78° C. was added n-BuLi (1.14 mL, 2.5 M in hexane, 2.84 mmol) dropwise over a 5 min. period. The resulting solution was stirred at this temperature for 0.5 h, warmed to 0° C. for 10 min., and then cooled back to −40° C. This lithiated amine solution was added dropwise to a solution (at −40° C.) of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.350 g, 0.811 mmol) in THF (15 mL) over 5 min. The final mixture was stirred at −40° C. for 15 min. and then warmed to room temperature for 15 min. At this point, the reaction mixture was quenched with H2O (20 mL) and diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/hexane gradient) to afford the product (0.347 g, 82%) as a solid; 1H NMR (CDCl3) δ 1.44-1.68 (bs, 1H), 2.01 (t, J=7.0 Hz, 2H), 2.74 (t, J=7.7 Hz, 2H), 3.27-3.46 (m, 4H), 3.53 (dd, J=7.7, 14.7 Hz, 2H), 5.94-6.08 (bs, 1H), 7.02-7.13 (m, 1H), 7.13-7.33 (m, 4H), 7.33-7.46 (m, 4H), 7.46-7.54 (m, 2H), 7.61 (s, 4H); mass spectrum [(+) APCI], m/z 520/522 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[NH2:12][C:13]([CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=2)[CH2:21]1)([CH3:19])[C:14](OCC)=[O:15]>C(OCC)(=O)C>[NH2:12][C:13]([CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=2)[CH2:21]1)([CH3:19])[CH2:14][OH:15]
Reactant: CCOC(=O)C(C)(N)C1CCc2cc(OC)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(C(C)(N)CO)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a 2 L flask cooled by ice water was added 60 g LiAlH4, and 1 L of THF. When the mixture was cooled to below 10° C., a mixture of 118.8 grams of ethyl 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate and 350 mL THF was added dropwise. No starting material remained by HPLC. The temperature was kept below 30° C. while 100 mL ethyl acetate was added. To the concentrated mixture was added 400 mL ethyl acetate, followed by 25 mL ice water. The mixture was filtered, and the filter cake with 300 mL ethyl acetate. The combined organic layers washed with brine 100 mL×2, dried with Na2SO4, decolorized with carbon and concentrated. To the oil, was added ether, the mixture stirred for overnight, filtered and dried to afford 50 g of 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O:38]=[C:39]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:40][C:41](O)=[O:42].C(Cl)CCl>CN(C=O)C>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:39](=[O:38])[NH:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 46 (333 mg, 0.631 mmol) in DMF (8 mL) at RT was added 3-oxo-3-(phenylamino)propanoic acid (226 mg, 2 eq, 1.262 mmol) and EDC (242 mg, 2 eq, 1.262 mmol), and the reaction mixture was stirred at RT for 24 hours. It was then concentrated to dryness then purified by column chromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), to afford 47a (357 mg, 82% yield) as a white solid. MS (m/z): 689.4 (M+H).