Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH2:21]>CCO>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[N:21][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccc(C=O)c1
Reactant: CN
Solvent: CCO
Product: CN=Cc1cccc(OCCO[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C
Yield: 87.89 %

Procedure:
3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (2.375 g, 8.47 mmol) was dissolved in 10 mL EtOH. MeNH2 (1.2 mL, 40% in H2O) was added and the mixture was heated to 40° C. for 30 min. The mixture was then concentrated in vacuo. The aqueous residue was diluted with isopropanol and then concentrated in vacuo. This was repeated twice more giving 2.184 g (87.89%) of a dry white powder.
Reaction SMILES: [F:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(F)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCc2sc(F)nc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from step A (100 mg, 0.456 mmol) in a mixture of THF (1.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide (0.558 mL of a 1 M soln, 0.588 mmol) and the resulting mixture stirred at room temperature for 90 mins. 1N HCl (0.558 mL, 0.558 mmol) was added and the mixture evaporated to dryness. The resulting crude product was used immediately without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4[N+](=O)[O-])cc3)c2cc1OC
Yield: 84.7 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (123 mg) was dissolved in toluene (12 ml) with heat, 4-chloro-2-nitrophenyl isocyanate (172 mg) was added, and the admixture was refluxed with heat for 14 minutes. The separated crystals were filtered and then washed with toluene to obtain 174 mg of the title compound (yield: 85%).
Reaction SMILES: CS(O[C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].[ClH:29]>C(O)(C)C.CCOCC>[ClH:29].[C:24]([NH:28][C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)(C)NC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of 1-benzhydryl-3-methylazetidin-3-yl methanesulfonate (2.00 g, 6.23 mmol) in iso-propanol (10 ml) was added tert-butyl amine (1.36 g, 18.63 mmol). The mixture was heated at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The residue was slurried with ethyl acetate and filtered, washing with further ethyl acetate and then concentrated to give a solid. The solid was slurried in ether and hydrochloric acid (20 ml, 2M in ether) was added, then stirred for 10 mins and filtered to provide the title compound as a tan solid (1.69 g, 74%). 1H NMR (DMSO) 1.40 (9H, s), 1.99 (3H, s), 3.85 (2H, brs), 4.11 (2H, brs), 4.71 (1H, brs), 7.35-7.50 (6H, m), 7.70-7.81 (4H, m), 10.23 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[C:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37](O)=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
177 mg of compound 37 was obtained in a similar manner to those described in the Examples 1 and 2 using 513 mg of ethyl 4-(2-aminophenoxy)butyrate and 400 mg of 3-[1-(4-tert-butylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1cccc(O)c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCCCCCBr)c1
Yield: 71.2 %

Procedure:
A mixture of 3-hydroxybenzamide (0.5 g, 3.65 mmol), 1,5-dibromopentane (1.82 g, 1.1 ml, 7.3 mmol) and potassium carbonate (500 mg, 3.65 mmol) was refluxed (2 h) in acetonitrile (18 ml) until the reaction was complete by TLC. The solvent was then removed by rotary evaporation to leave a white sticky solid which was chromatographed (10% methanol in dichloromethane on silica) to give a white solid. This was recrystallised from a mixture of petrol and ethyl acetate to give white flaky crystals (0.744 g, 2.6 mmol, 70% yield). mp 98-99° C.
Reaction SMILES: [CH3:1][C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=O.[CH3:29][C@@H:30]([C@@H:36]1[C@@:40]2([CH3:57])[C@@H:41]([OH:56])[CH2:42][C@@H:43]3[C@@:48]4([CH3:54])[CH2:49][CH2:50][C@@H:51]([OH:53])[CH2:52][C@H:47]4[CH2:46][C@@H:45]([OH:55])[C@H:44]3[C@@H:39]2[CH2:38][CH2:37]1)[CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[CH3:29][C@@H:30]([C@@H:36]1[C@@:40]2([CH3:57])[C@@H:41]([OH:56])[CH2:42][C@@H:43]3[C@@:48]4([CH3:54])[CH2:49][CH2:50][C@@H:51]([OH:53])[CH2:52][C@H:47]4[CH2:46][C@@H:45]([OH:55])[C@H:44]3[C@@H:39]2[CH2:38][CH2:37]1)[CH2:31][CH2:32][C:33]([O:35][CH3:1])=[O:34]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
A process for preparing chenodeoxycholic acid from cholic acid comprising the steps of: (1) esterification of the acid group of the cholic acid to produce methyl cholate; (2) selective acetylation of the methyl cholate to produce methyl 3,7-diacetyl cholate; (3) mesylation of the methyl 3,7-diacetyl cholate to produce methyl 3,7-diacetyl-12-mesylcholate; (4) dehydromesylation of the methyl 3,7-diacetyl-12-mesylcholate by hexamethylphosphoric triamide in the presence of a weak base to produce methyl 3,7-diacetylchol-11-enate; (5) hydrogenation of the methyl 3,7-diacetylchol-11-enate to produce methyl diacetyl chenodeoxycholate; and (6) saponification of the methyl diacetyl chenodeoxycholate to produce chenodeoxycholic acid.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:21]([O:23][NH2:24])[CH3:22]>CO>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCCC(=O)C1=C(O)CC2(CSCCSC2)OC1=O
Reactant: CCON
Agent: Cl
Solvent: CO
Product: CCCC(=NOCC)C1=C(O)CC2(CSCCSC2)OC1=O
Yield: 32.8 %

Procedure:
The acylated compound (8.52) (0.453 g, 1.50 mmol) was oximated with ethoxyamine hydrochloride (0.195 g, 2.00 mmol) in methanol (10 ml) as described in Part (c) of the general procedure above to afford a product which was recrystallized from ether to give the title compound (6.25) (0.170 g, 33%) as white microcrystals m.p. 108°-110° C. Mass spectrum m/z 346 (M+1). 1H n.m.r. δ(CDCl3) 4.11, q, J 7 Hz, OCH2CH3 ; 3.95-1.1, complex, 14H; 1.33, t, J 7 Hz, OCH2CH3 ; 1.00, t, J 7 Hz CH2CH2CH3.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Na].C1COCC1.Cl[C:15]1[N:19]([C:20]([CH3:22])=[CH2:21])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[N:16]=1>O>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][C:15]1[N:19]([C:20]([CH3:22])=[CH2:21])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[N:16]=1
Reactant: OCCCCCO
Reactant: C=C(C)n1c(Cl)nc2ccccc21
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)n1c(OCCCCCO)nc2ccccc21
Temperature: 25 °C
Yield: 51 %

Procedure:
3.3 g of 1,5-pentanediol and 0.4 g of sodium were stirred under nitrogen atmosphere for 30 minutes with heating. After the sodium disappeared, the reaction mixture was added dropwise with 30 ml of anhydrous THF containing 2.9 g of 2-chloro-1-isopropenylbenzimidazole and then refluxed for 8 hours. After cooling to room temperature, the mixture was added with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2 g of the title compounds (yield: 51%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[N:17]=[N:18][C:13]([CH2:12][CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: CCCC[C@H]1CC[C@H](CCc2ccc(=O)[nH]n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC[C@H]1CC[C@H](CCc2ccc(Cl)nn2)CC1
Temperature: 0 °C

Procedure:
21.0 g of 6-[2-(trans-4-butylcyclohexyl)ethyl]-3(2H)-pyridazinone are treated with 20 ml of phosphorus oxychloride and slowly heated to reflux. After boiling under reflux for 20 minutes, the excess phosphorus oxychloride is distilled off. The residue is cooled 0° C., hydrolyzed cautiously with 100 g of crushed ice, then neutralized with sodium hydrogen carbonate and extracted three times with 100 ml of tert.butyl methyl ether each time. The combined organic phases are dried over sodium sulphate and freed from solvent on a rotary evaporator. The crude product of 3-chloro-6-[2-(trans-4-butylcyclohexyl)ethyl]pyridazine obtained is recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[N:15]1[N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=12
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Cc1ccc(N)c(Br)n1
Product: Cc1ccc(N)c(C#CCCn2nc3ccccc3n2)n1
Yield: 44.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methyl-pyridin-3-ylamine (80 mg, 0.43 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (73 mg, 0.43 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 53 mg (0.19 mmol, 45%) of 2-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-6-methylpyridin-3-amine as a brown solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]1[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]1=[O:28])[CH2:12][CH2:11][CH2:10]2>CCOC(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]1[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:26][CH:27]=3)[C:18]1=[O:28])[CH2:12][CH2:11][CH2:10]2
Reactant: O=C1[C@@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C1[C@@H](N2CCCc3cc(Cl)ccc32)CCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 50 °C
Yield: 61 %

Procedure:
Prepared using general procedure 62: To chlorosulfonic acid (15 mL, 220 mmol) at 0° C. under N2 was added (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-phenylpyrrolidin-2-one (2.43 g, 7.4 mmol) in portions. The reaction mixture was heated to 50° C. for 15 min. and, after cooling to RT, carefully poured onto ice-water (500 mL). EtOAc (150 mL) was added, the phases were separated, and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 50-80% EtOAc in hexane gave 4-((S)-3-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-benzene-1-sulfonyl chloride as an off-white solid (1.92 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J=2.1, 6.8 Hz, 2H), 7.61 (dd, J=2.1, 6.8 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 6.77 (d, J=8.7 Hz, 1H), 5.01-4.96 (m, 1H), 3.85-3.81 (m, 2H), 3.17 (t, J=5.6 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 2.42-2.32 (m, 1H), 2.15-2.08 (m, 1H), 1.92-1.79 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=425.1; tR=4.03 min
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH:12]=C.C1(=O)OCC1.C([NH-])C=C>>[CH2:12]([CH:3]1[CH2:4][CH2:5][O:6][C:1](=[O:7])[CH2:2]1)[CH2:11][CH:10]=[CH2:9]
Reactant: O=C1CCCCO1
Reactant: C=CCCCBr
Agent: C=CC[NH-]
Agent: O=C1CCO1
Product: C=CCCC1CCOC(=O)C1
Yield: 65.4 %

Procedure:
10.09 g of tetrahydro-4-(3-butenyl)-2H-pyrane-2-one of interest was prepared in the same manner as in Example 1 except that 10.01 g (100.0 mmol) of δ-valerolactone and 17.88 g (110.0 mmol) of 5-bromo-1-pentene were used instead of β-propiolactone and allyl amide described in Preparation Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:20]>CO>[ClH:20].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: Brc1ccc(C2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The suspension of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.2 g, 3.7 mmol) in anhydrous methanol (10 mL) was added hydrogen chloride in methanol (20 mL, 4.0M in MeOH) under nitrogen. The reaction was stirred at room temperature for 1.5 hours. The mixture was concentrated to afford the title compound (0.99 g, quantitative yield) which was used without purification in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6](N2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1.[Br:37]C1C([C@@H](N[S@](C(C)(C)C)=O)CC2C=C(F)C=C(F)C=2)=NC(Br)=CC=1>>[Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][C:5]([Br:37])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br

Procedure:
The title compound was prepared according to the 2 step method presented for the synthesis of compound 30E of Example 30 utilizing 42D.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CNCCO
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(CCO)CCCCl
Yield: 56.5 %

Procedure:
2-(Methylamino)-ethanol (1.0 g, 13.3 mmol), acetone (20 ml, 20 vol), 5M NaOH solution (3.19 ml, 1.2 eq.) and 1-bromo-3-chloropropane (6.28 g, 39.9 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.14 g, 55%) as a colourless oil.
Reaction SMILES: C[Mg]Br.Br[C:5]1[CH:19]=[CH:18][C:8](C=NS(C(C)(C)C)(=O)=[O:12])=[CH:7][C:6]=1F.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:18][CH2:19][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][CH2:23][O:24][C:25]([CH3:21])=[O:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)S(=O)(=O)N=Cc1ccc(Br)c(F)c1
Agent: C[Mg]Br
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 2 h

Procedure:
Under inert gas atmosphere 37.2 mL (112 mmol) of a 3N solution of methyl magnesium bromide in THF are added dropwise to 17.1 g (55.8 mmol) 2-methyl-propane-2-sulfonic acid 4-bromo-3-fluoro-benzylideneamide (IX.1) in 170 mL THF at −78° C. The cooling bath is removed and stirring is continued for 2 h. After that time, the mixture is poured into sat. NH4Cl-solution (300 mL) and extracted with EtOAc. The organic layer is separated, washed with brine and dried over sodium sulphate. The solvent is removed by evaporation to yield the desired product.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9](C1C=CC=CC=1)[C:10](=[O:14])[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:49]=1[OH:59]>C1COCC1>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:21])[C:2]=1[NH:9][C:10](=[O:14])[C:11]([NH:47][C:48]1[CH:53]=[C:52]([CH3:54])[CH:51]=[C:50]([C:55]([CH3:57])([CH3:56])[CH3:58])[C:49]=1[OH:59])=[O:13]
Reactant: Cc1cc(C)c(N(C(=O)C(=O)O)c2ccccc2)c(C)c1
Reactant: Cc1cc(N)c(O)c(C(C)(C)C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cc(C)c(NC(=O)C(=O)Nc2cc(C)cc(C(C)(C)C)c2O)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
N-(Mesityl)-oxanilic acid (2.15 g, 10.4 mmol, 1.0 eq), prepared according to the synthesis method described in Example 5, and 1-hydroxybenzotriazole (2.39 g, 15.6 mmol, 1.5 eq) were added to an oven dried, two-necked flask, forming a solution. THF (100 ml) was then added and the solution was cooled to 0° C. 1,3-dicyclohexylcarbodiimide (1 M in CH2Cl2) (12.5 ml, 12.5 mmol, 1.2 eq) was then added to the solution. The solution was then allowed to stir at 0° for one hour. During this time, a white precipitate formed. 2-amino-4-methyl-6-tert-butylphenol (1.863 g, 10.4 mmol, 1.0 eq), prepared according to the synthesis method described in Example 6, was then added to the suspension. The suspension was then allowed to stir overnight. The next day, the solvent was removed under reduced pressure, and ethyl acetate was added. The resulting suspension was then filtered to remove the solid. The filtrate was washed with 10% citric acid solution (2×50 ml), 5% NaHCO3 (2×50 ml) and brine (50 ml). It was dried over MgSO4, and the solvent was removed under reduced pressure, leaving a solid which was recrystallized from hexane to give the product as a white solid (2.92 g, 7.9 mmol, 76% yield). 1H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 8.77 (s, 1H), 7.84 (s, 1H), 7.05 (d, J=1.8 Hz, 1H), 6.92 (m, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 2.22 (s, 6H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.5, 157.4, 146.2, 140.6, 138.1, 134.9, 129.9, 129.6, 129.4, 126.9, 124.9, 121.4, 35.3, 30.0, 21.2, 21.0, 18.5. Anal. Calcd for C22H28N2O3: C, 71.71; H, 7.66; N, 7.60. Found: C, 72.01; H, 8.03; N, 7.36.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[CH:18]([O:26][C:27](=[O:29])[CH3:28])[CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][Br:33])=[CH:21][C:20]3[C:19]([CH3:25])([CH3:24])[CH:18]([O:26][C:27](=[O:29])[CH3:28])[CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2C)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A solution of 0.68 g (1.57 mmol) of Ethyl-4-[(E)-2-(5,5,8,8-Tetramethyl-3-methyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 0.36 g (2.03 mmol) of N-bromosuccinimide and 0.019 g (0.078 mmol) of benzoyl peroxide in 15 mL of carbon tetrachloride was heated at reflux. After 3 hours the reaction was cooled to room temperature, washed with 10% aqueous sodium bisulfite and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution, hexane-5% ethyl acetate/hexane) to give 0.45 g (56%) of Ethyl-4-[(E)-2-(5,5,8,8-Tetramethyl-3-bromomethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+=512).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([Cl:19])[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:5]([CH3:20])[CH:4]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:5]([CH3:20])[CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)c3sccc3n2)c(C)c1
Reactant: CNc1ccccc1
Solvent: CCOCC
Product: COc1ccc(Nc2nc(N(C)c3ccccc3)c3sccc3n2)c(C)c1
Product: Cl
Yield: 85.5 %

Procedure:
2-(4-Methoxy-2-methylphenylamino)-4-chlorothieno[3,2-d]pyrimidine (4 g, 0.013 mol) and N-methylaniline (2.8 g, 0.026 mol) were heated at 140° for 1 hour. The addition of diethyl ether gave a solid which was collected by filtration and dried, (5.5 g). Recrystallization from ethanol/diethyl ether gave the title compound, (4.59 g), m.p. 225°-227°.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[CH:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:2]3[C:3]4[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:24][CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: NC1CCN(CC2CCCCC2)CC1
Reactant: Cc1sc2ncnc(Cl)c2c1C
Agent: Cl
Product: Cc1sc2ncnc(NC3CCN(CC4CCCCC4)CC3)c2c1C

Procedure:
The title compound was prepared (81 mg, 28%) from 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine (325 mg, 1.21 mmol) and 1-(cyclohexylmethyl)piperidin-4-amine dihydrochloride (160 mg, 0.81 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 5.36 (d, 1H), 4.22 (m, 1H), 2.80 (d, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.21-2.09 (m, 7H), 1.79-1.45 (m, 6H), 1.20 (m, 4H), 0.88 (m, 2H); MS (ESI) m/z: Calculated for C20H31N4S, 359.23; Observed: 359.2 (M++1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1.[Li+].[BH4-]>C1COCC1>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[C:10]#[N:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C#N)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1OCc1ccccc1
Temperature: 70 °C

Procedure:
3-Benzyloxy-4-cyano-benzoic acid methyl ester from step 1 (400 mg, 1.5 mmol ) was dissolved in THF (7.5 ml). LiBH4 in THF (2 M, 1.5 ml, 3 mmol) was added. The reaction mixture was heated at 70° C. for 3 hours. The reaction was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.