Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]2[C:15]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:13]([O:21][CH3:22])=[CH:12][C:10]=2[N:11]=1>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCOCC1>[CH2:19]([NH:18][C:16]([C:15]1[C:9]2[S:8][C:7]([NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[N:11][C:10]=2[CH:12]=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:17])[CH3:20]
Reactant: CCN=C=O
Reactant: CCNC(=O)c1cc(OC)cc2nc(N)sc12
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(OC)cc(C(=O)NCC)c2s1
Temperature: 60 °C

Procedure:
Ethyl isocyanate (0.87 mL, 10.9 mmol) was added to a suspension of 2-amino-N-ethyl-5-methoxy-1,3-benzothiazole-7-carboxamide (549 mg, 2.18 mmol) and dibutyl tin diacetate (4 drops, catalytic amount) in dioxane (12 mL). The reaction was heated to 60° C. for 8 hours after which time LCMS indicated clean conversion to the desired product. The reaction solvent was removed in vacuo and the crude material used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)C.O>[Fe].C(O)(=O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][C@@H:24]1[CH2:28][CH2:27][O:26][CH2:25]1)[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Temperature: 25 °C

Procedure:
A mixture of 12.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((R)-tetrahydrofuran-3-yloxy)quinazoline, 200 ml of ethanol, 100 ml of water, and 17.20 ml of glacial acetic acid is heated to reflux temperature. Then a total of 7.00 g of iron powder is added in batches. The reaction mixture is refluxed for about four hours and then cooled to ambient temperature overnight. For working up, the reaction mixture is evaporated using the rotary evaporator. The residue is taken up in methylene chloride/methanol (9:1), mixed with 20 ml of concentrated ammonia solution and filtered through a layer of silica gel. It is washed with copious amounts of methylene chloride/methanol (9:1) and the combined filtrates are evaporated down. The residue is stirred with diethylether and suction filtered. Yield: 8.59 g (73% of theory); mass spectrum (ESI−): m/z=373, 375 [M−H]−; Rf value: 0.27 (silica gel, ethyl acetate/methanol=9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:30]=[C:29]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])[CH2:28][CH2:27][CH2:26][C:22]1[S:21][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)CCCc1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a stirring 5 mL dichloromethane (DCM) solution of 0.29 g (one mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, and 0.17 g (one mmol) of 4-(2-thienyl)butyric acid cooled to 5° C. was added 0.23 g (1.1 mmol) of dicyclohexylcarbodiimide. With warming to room temperature, the reaction was stirred for 18 hours. The reaction mixture was filtered through a sintered-glass funnel. The filtrate was dried under water aspirator vacuum. The resultant solid product was chromatographed as described previously. Analysis calculated for C22H20N3O3SCl (M.W. 441.94): C, 59.79; H, 4.56; N, 9.51; Cl, 8.02. Found: C, 59.77; H, 4.62; N, 9.51; Cl, 8.23.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Br[CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]>C(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[CH3:1]
Reactant: CNCCO
Reactant: N#Cc1cccc(CBr)c1
Solvent: ClCCl
Product: CN(CCO)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a solution of 2-(methylamino)ethanol (4 mL, 51 mmol) and TEA (4 mL, 28.05 mmol) in DCM (75 mL) under N2, was added 3-(bromomethyl)benzonitrile (5 g, 25.50 mmol) at 0° C. and the mixture was stirred at RT for 30 min. After this time, reaction mixture was concentrated under reduced pressure and the remaining residue was dissolved in DCM and washed with water to give the title compound as a colorless liquid (4.9 g, 100%). 1H NMR (DMSO-d6, 400 MHz) δ 7.76 (s, 1H), 7.69-7.71 (m, 2H), 7.63-7.65 (m, 1H), 7.49-7.53 (m, 1H), 4.41-4.43 (m, 1H), 3.47-3.51 (m, 2H), 3.32 (m, 2H), 2.40-2.43 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[NH2:10][C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1>CN1C(=O)CCC1.O>[NH2:10][C:11]1[N:16]=[C:15]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1
Reactant: CCCC[C@H](N)CCO
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
(S)-3-Aminoheptan-1-ol (0.135 g) was added to a stirred solution of the product from step (iii) (0.12 g) in NMP (2 mL). The mixture was heated at 150° C. for 48 h, and then at 17° C. for a further 8 h. The mixture was allowed to cool, diluted with water (10 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried and evaporated.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53]>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:53])([F:54])[F:55])[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 1-(bromomethyl)-2-(trifluoromethyl)benzene. MS (m/e): 456.4 (MH+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(C=O)C4)c3)ncnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(CO)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile prepared as in Example 97, Step 4 (50.0 mg, 0.108 mmol) in methanol (280 μL) was cooled to 0° C., then sodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction was held at 0° C. for 10 minutes, at which point LCMS and TLC indicated complete reaction. The reaction was quenched by cautious addition of 1N HCl (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO3 and CHCl3. The phases were separated and the aqueous phase was washed with additional CHCl3. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 1H NMR (400 MHz, CDCl3): 8.84 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), −0.059 (s, 9H). MS (EI) m/z=467.2 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:21]([CH:30]3[CH2:35][CH2:34][N:33](C(N4CCOCC4)=O)[CH2:32][CH2:31]3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:21]([CH:30]3[CH2:35][CH2:34][N:33]([C:7]([N:3]4[CH2:4][CH2:5][NH:6][C:2]4=[O:1])=[O:8])[CH2:32][CH2:31]3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(Cl)N1CCNC1=O
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)N4CCOCC4)CC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)N4CCNC4=O)CC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1Cl

Procedure:
Prepared from intermediate product A1 and 2-oxo-imidazolidine-1-carbonyl chloride as described for compound 1. M. p. 216–218° C.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5].[CH2:15](OC(=O)[C@@H]1CCCN1C(=O)CCS)C>>[CH3:15][S:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)CCS
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(N)=O
Product: CSCC(C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline amide for the 1-(3-mercaptopropanoyl)-L-proline ethyl ester in the Procedure B of Example 80 and eliminating the saponification step, 1-(3-methylthio-2-methylpropanoyl)-L-proline amide is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH:25]([CH3:32])[CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([Cl:33])=[CH:20][N:19]=1>>[Cl:33][C:21]1[C:22]([NH:24][CH:25]([CH3:32])[CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NC(C)CNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-propyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-propyl]-methanesulfonamide in an analogous manner to Example 302. Product isolated as a white foam (117 mg, 71%). LCMS (m/e) 483 (M+1); 1H-NMR (CDCl3, 400 MHz) δ7.94 (s, 1H), 7.32 (d, 1H, J=8.0 Hz), 7.24 (s, 1H), 7.04 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 5.35-5.27 (m, 1H), 5.22 (d, 1H, J=7.0 Hz), 4.41-4.31 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.46-3.35 (m, 1H), 3.38 (s, 3H), 3.29-3.20 (m, 1H), 2.96-2.86 (m, 4H), 2.91 (s, 3H), 2.80-2.68 (m, 6H), 1.36 (d, 3H, J=6.7 Hz).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[CH:9][CH:10]=1)[NH2:8].C([Br:19])C1C=CC=CC=1>>[F:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[CH:9][CH:10]=1)[NH:8][Br:19]
Reactant: Cc1cc(F)ccc1N
Reactant: BrCc1ccccc1
Agent: BrBr
Product: Cc1cc(F)ccc1NBr

Procedure:
Bromine (0.5 mole) is added over 1 hour to stirred 4-fluoro-2-toluidine (0.5 mole) at 100° C. illuminated with a high wattage lamp. The crude benzyl bromide is used as prepared.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1O.C1(O)C2=C3C(=CC=C2)C=CC=C3C1.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][CH:35]=CC=1>>[C:26]1([OH:25])[C:27]2[C:28](=[CH:35][CH:36]=[CH:37][CH:32]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Oc1ccccc1-c1ccccc1
Agent: OC1Cc2cccc3cccc1c23
Agent: Oc1ccc2ccccc2c1
Product: Oc1cccc2ccccc12

Procedure:
2-naphthol; 1-acenaphthenol; 2-hydroxybiphenyl;
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@:4]([CH3:29])([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:5][C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7].[Li+].[OH-]>O1CCOCC1>[CH:10]12[CH2:18][CH:14]3[CH2:13][CH:12]([CH2:17][CH:16]([CH2:15]3)[CH:9]1[O:8][C:6]([NH:5][C@@:4]([CH3:29])([C:3]([OH:30])=[O:2])[CH2:19][C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=1)=[O:7])[CH2:11]2
Reactant: COC(=O)[C@@](C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@](Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a stirred solution of N-[(2-adamantyloxy)carbonyl]-α-methyl-D-tryptophan methyl ester (1.36 g, 3.3 mmol) in aqueous 1,4-dioxan (1:2) (20 mL) was added an excess of LiOH (0.210 g, 5 mmol) and stirred at room temperature overnight. After removing the solvent in vacuo the residue was chromatographed using 5% MeOH:95% CH2Cl2 then 10% MeOH:90% CH2Cl2 as eluants to yield the acid (0.953 mg, 90%) as a white solid, crystallized from n-hexane, mp 210°-215° C. (EtOAc/n-hexane); IR (film) 1689 cm-1 ; NMR (CDCl3 -D2O), δ1.3-2.2 (14H, m), 1.70 (3H, s), 3.26 (1H, d, J 13.5 Hz), 3.63 (1H, d, 13.5 Hz); 4.77 (1H, br.s), 6.85-7.60 (5H, m).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([C:25]2[CH:26]=[C:27]([C:32]([NH2:34])=[NH:33])[S:28][C:29]=2[S:30][CH3:31])(=[O:24])=[O:23])[CH:17]=1.B(Br)(Br)Br>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([C:25]2[CH:26]=[C:27]([C:32]([NH2:34])=[NH:33])[S:28][C:29]=2[S:30][CH3:31])(=[O:24])=[O:23])[CH:17]=1
Reactant: COc1ccccc1-c1cccc(S(=O)(=O)c2cc(C(=N)N)sc2SC)c1
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccccc2O)c1
Yield: 77 %

Procedure:
4-(2′-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (46 mg, 0.086 mmol, as prepared in Example 34, step a) was treated with BBr3 (1 M in DCM) for 18 hr at rt. The reaction was quenched with MeOH at 0° C. and then concentrated in vacuo to a solid. Purification of this solid using C18-HPLC (10–80% CH3CN in H2O (0.1% TFA) over 25 min) afforded 34 mg (77%) of the title compound as a white solid. 1H-NMR (CD3OD): δ 8.30 (s, 1H), 8.27 (t, 1H, J=1.9 Hz), 7.89–7.96 (m, 2H), 7.61 (t, 1H, J=7.9 Hz), 7.26–7.30 (m, 1H), 7.19–7.24 (m, 1H), 6.90–6.95 (m, 2H), 2.70 (s, 3H). ESI-MS (m/z): Calcd. for C18H16N2O3S3: 405.5 (M+H); found: 405.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=2)[N:10]=1)([CH3:5])[CH3:4].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:25]([NH:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=2)[N:10]=1)([CH3:5])[CH3:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(CNCc1ccccc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A solution of Example 3 (103 mg, 0.3 mmol) and benzaldehyde (30.7 mg, 0.3 mmol) in methanol (1 ml) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (76.3 mg, 0.36 mmol) was then added and the mixture stirred at room temperature for 3 hours before being diluted with ethyl acetate and sodium hydrogen carbonate solution. The aqueous layer was separated and re-extracted with additional ethyl acetate. The combined organic layers was then washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/0.880 ammonia solution (20:1:0.1) to give the title compound (22 mg, 17%) as a pale yellow solid; MS(ES+) m/e 433/435 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1NC(C)(C)N(C)[C:10]1=[O:17])[C:3]1C=CC=CC=1.[C:18]1([C:24]2[O:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:27]3[C:32]=2[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.C(=O)/C=C/C>CN(C=O)C.O.CCOCC>[C:18]1([C@@:24]23[O:25][C@@:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C@@H:9]([CH:10]=[O:17])[C@@H:2]2[CH3:3])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]3=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: C/C=C/C=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H]1[C@H](C=O)[C@]2(c3ccccc3)O[C@@]1(c1ccccc1)c1ccccc12
Temperature: 10 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 10° C. solution of 5 (13 mg, 0.058 mmol), 1,3-diphenylisobenzofuran (162 mg, 0.60 mmol), and MeOH (12 μL, 0.30 mmol) in DMF/H2O (95/5 v/v, 1.0 M) was added (E)-crotonaldehyde (25 μL, 0.30 mmol). The solution was stirred at 10° C. for 24 h. The reaction mixture was then diluted with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer was extracted with Et2O (10 mL×2) and the combined organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (7% EtOAc/hex) afforded the title compound as a yellow solid in 75% yield (76 mg, 0.22 mmol); 35:1 exo:endo; 96% ee. Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, EtOH (0.1 M)), by HPLC (Chiralcel OD-H column, 3% EtOAc/hex, 1.0 mL/min) exo isomers tr=14.1 min and 15.3 min, endo isomers tr=16.5 min and 20.8. IR (CH2Cl2) 3066, 3041, 2828, 2729, 1722, 1603, 1499, 1457, 1448, 1381, 1355, 1309 cm−1; 1H NMR (500 MHZ, CDCl3)δ9.36 (d, J=5.8 Hz, 1H, CHO), 7.73-7.78 (m, 2H, ArH), 7.43-7.57 (m, 7H, ArH), 7.35-7.40 (m, 1H, ArH), 7.16-7.26 (m, 3H, ArH), 7.04-7.08 (m, 1H, ArH), 3.08 (dq, J=6.9,4.1 Hz, 1H, CHCH3), 2.56 (dd, J =5.8, 4.2 Hz, 1H, CHCHO), 0.96 (d, J=6.9 Hz, 3H, CH3); 13C NMR (125 MHZ)δ201.9, 147.4, 145.0, 145.0, 136.6, 135.7, 135.5, 128.8, 128.6, 128.0, 127.4, 127.3, 127.0, 126.0, 125.5, 121.7, 118.5, 91.4, 89.2, 66.0, 43.0, 34.2, 30.3, 16.5; HRMS exact mass calcd for (C24H20O2) requires m/z 341.1541, found m/z 341.1542; [α]D=−82.4 ©=1.0, CHCl3).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C[O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
14 ml of dihydropyran was added dropwise to a mixture of 17.8 g of 4-methoxycinnamic acid, 0.34 g of 4-toluene sulphonic acid and 100 ml of diethyl ether under a nitrogen atmosphere. After one hour stirring the solution became transparent. 150 ml of ether was added and it was extracted with 200 ml of 5% of sodium hydroxide solution and evaporated using a rotary evaporator. The residue was mixed with 50 ml of ethanol and a solution of 8 g of KOH in 50 ml of water and was refluxed for 1 hour upon which a transparent solution was obtained. It was cooled with 150 g of crushed ice. Then 50 ml of HCl (2.5 N) was added dropwise to the solution until pH=4 upon which a solid precipitated. It was filtered off and washed with water. The product was dried in a dessicator over silica. 19.59 g (yield 79%) of a white solid was obtained.
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O.[Li]N([Si](C)(C)C)[Si](C)(C)C>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:5]2[S:6][C:2]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)([CH3:1])[C:3](=[O:17])[N:4]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: CC1SC(N[C@@H](C)c2ccc(F)cc2)=NC1=O
Reactant: CC(C)(O)c1ccc(Br)cc1
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(C)(C)O)cc2)S1)c1ccc(F)cc1

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(4-fluorophenyl)ethylamino)thiazol-4(5H)-one with 2-(4-bromophenyl)propan-2-ol using the procedure described for 2a. 4.0 equivalents of LiN(SiMe3)2 was used. MS (ESI, pos. ion) m/z: 387 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH2:12]([N:2]([CH2:9][C:5]1[CH:6]=[CH:10][CH:11]=[CH:3][CH:4]=1)[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH:8]=[CH:9][C:5]=2[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc2occc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2ccc3occc3c2)cc1

Procedure:
A stirred solution of 5-aminobenzo[b]furan hydrochloride in dry DMSO is treated with excess benzyl bromide followed by solid NaHCO3 to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:8][CH2:9][CH3:10])[CH2:6][NH2:7])[CH3:3].[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][C@H:17]1[CH2:21][C:20](OCC)=[N:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][C@@H:17]1[CH2:18][N:19]=[C:20]([NH:7][CH2:6][CH:5]([O:8][CH2:9][CH3:10])[O:4][CH2:2][CH3:3])[CH2:21]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC1=NC[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(CNC1=NC[C@@H](O[Si](C)(C)C(C)(C)C)C1)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 434.4 %

Procedure:
Ethanolic hydrogen chloride (1M, 420 mL) was added dropwise to a solution of aminoacetaldehyde diethyl acetal (55.1 g, 0.14 mol) and the compound isolated in Step 2 (101 g, 0.41 mol) in ethanol (1500 mL). This mixture was stirred at room temperature for 16 hours, and then evaporated under reduced pressure. The resulting solid was recrystalised from ether to give [(S)-4-(tert-butyl-dimethyl-silanyloxy)-4,5-dihydro-3H-pyrrol-2-yl]-(2,2-diethoxy-ethyl)-amine as a solid (201 g, 78%).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:12])[CH2:8][CH:9]=[N:10]O>C(O)(=O)C.[Zn]>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:12])[CH2:8][CH2:9][NH2:10]
Reactant: CC(CC=NO)c1ccccc1-c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(CCN)c1ccccc1-c1ccccc1
Reaction time: 4 h

Procedure:
1.5 g of zinc dust are added, while stirring, to a solution of 2.39 g of 3-p-biphenylyl-butanaldoxime in 25 ml of acetic acid. The mixture is stirred for a further 4 hours, filtered, diluted with water, rendered alkaline with ammonia and extracted with chloroform. After the customary working up, 3-p-biphenylyl-butylamine is obtained. Hydrochloride, m.p. 226°-228°.