Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>O.CN(C)C=O>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: COC(=O)Nc1ccc(O)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A solution of 3.6 g of potassium hydroxide in 10 ml of water was added to a solution of 10.0 g of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in Example 15(a) above] in 30 ml of dimethylformamide and 6 ml of water cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 20 minutes, and then a solution of 10.0 g of 2-chloromethylbenzothiazole in 25 ml of dimethylformamide was added to the reaction mixture. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 1 hour, at the end of which time the temperature was elevated further to 60° C. and the reaction mixture stirred for a further 2 hours. The reaction mixture was then poured into water to give a crystalline precipitate which was washed with water and further washed with diethyl ether and then recrystallised from ethyl acetate to give 10.5 g (yield 59%) of the title compound as a crystalline solid having a melting point of 147° to 149° C. The proton nuclear magnetic resonance spectrum was identical to that for the title compound of Example 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O.IC1C=CC(N)=CC=1>>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[C:6]([NH:16][C:17]1[CH:22]=[N:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:8]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: COc1ccc(N)cn1
Agent: Nc1ccc(I)cc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: COc1ccc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cn1

Procedure:
This compound was synthesized by the same procedure as for Example 15, except 3,4,5-trimethoxybenzoic acid and 5-amino-2-methoxypyridine were used instead of 2-napthoic acid and 4-iodoaniline. Tiny off-white needles. M+319.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11]1.[Li+].[Cl-].CC([O-])=O.[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]([C:12]3[CH:13]=[CH:14][O:10][CH:11]=3)=[C:16]([Si:17]([CH3:18])([CH3:20])[CH3:19])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C[Si](C)(C)C#Cc1ccoc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1[nH]c2ncc(Br)cc2c1-c1ccoc1
Yield: 22.1 %

Procedure:
5-Bromo-3-iodo-pyridin-2-ylamine (12) (390 mg, 1.32 mmol; prepared according to WO0196308), crude acetylene 11 (910 mg), LiCl (56 mg, 1.32 mmol), KOAc (259 mg, 2.64 mmol), Pd(OAc)2 (7.4 mg, 0.03 mmol) in DMF (10 mL) were heated in a sealed tube at 100° C. After 19 h the mixture was partitioned between Et2O and saturated aqueous NH4Cl. The organic layer was separated and the aqueous layer was extracted with Et2O (4×). The combined organic solutions were dried (MgSO4) and concentrated. The residual red oil was purified by PTLC with AcOEt:hexane=1:4 as eluent to yield azaindole 13 (97.9 mg, 22%) as an oil. 1H NMR (400 MHz; CDCl3) δ 0.32 (s, 9H), 6.53 (d, J=0.9 Hz, 1H), 7.51 (s, 1H), 7.55 (t, J=1.6 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 9.09 (brs, NH).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:22])[NH:12][C:13]1[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][N:17]=1)(=O)C.Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][N:17]=1)=[O:22]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ncc(S(C)(=O)=O)s1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc(NC(=O)c2ccccc2O)s1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of 7 (1.0 g, 2.94 mmol, 1.0 eq) dissolved in THF (20 mL) was added under stirring to 2M HCl (100 mL). The reaction was refluxed for one hour and allowed to cool under stirring over one hour. The product was filtered using a sintered glass funnel, washed with distilled water and THF and dried in high vacuum to afford 834 mg (95%) of 6 as a colorless solid.
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.F[C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][C:37]=1F)[O:16][C:17]1[C:18](=[O:34])[O:19][C:20]([CH3:33])([CH3:32])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=O)=O)=[CH:24][CH:23]=1>>[O:16]([C:17]1[C:18](=[O:34])[O:19][C:20]([CH3:32])([CH3:33])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:31])=[CH:24][CH:23]=1)[C:15]1[CH:14]=[CH:13][CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: O=C(O)COc1ccccc1
Product: CSc1ccc(C2=C(Oc3ccccc3)C(=O)OC2(C)C)cc1

Procedure:
Following the procedure described for example 1, Step 4, the title compound was prepared from phenoxyacetic acid and 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (example 1, Step 4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([OH:50])=[O:49])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[N+](C)C)C.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 19-{(S)-1-tert-Butoxycarbonyl-3-[2-(2-{[2-(2-carboxymethoxyethoxy)ethyl-carbamoyl]methoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}nonadecanoic acid tert-butyl ester (3.1 g) in acetonitrile (50 ml) was added TSTU (1.39 g) and DIPEA (0.91 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (100 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil. Yield 99% (3.4 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)(Cl)Cl>[CH2:37]([O:36][C:34]([NH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]=2[CH2:6][CH2:5]1)=[O:35])[CH3:38]
Reactant: NCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a cooled solution of 3-(2-aminoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 19b (5.5 g, 0.016 mole) and triethylamine (1.8g, 0.018 mole) in chloroform (75 ml) was slowly dropped a solution of ethyl chloroformate (2.0 g, 0.018 mole) in chloroform (25 ml). After stirring twenty hours at ambient temperature the reaction mixture was concentrated to a semisolid which was dissolved in ether, washed with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to yield an oil. A sample of the resultant oil was distilled to yield an oil of 3-(2-ethoxycarbonylaminoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, bp 235°-238° C./0.10 mm.
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=7[F:25])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6F)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(2-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (154 mg; compound B81) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (124 mg; compound C10) and HBTU (261 mg) in DCM/DMF (15 ml/1 ml) in the presence of DIPEA (324 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N#N.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(#N)C>[CH2:3]([N:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: CCCCCCCCBr
Agent: N#N
Solvent: CC#N
Product: CCCCCCCCN(C)Cc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
254.5 g Freshly distilled N-methylbenzylamine (2.1 mole, fw=121.18, ˜271 mL) is added to 350 mL stirring acetonitrile in a 1 L 4-neck round-bottom flask that is equipped with a heating mantle, mechanical stirrer, 250 mL addition funnel, reflux condensor and teflon-coated thermocouple. The reaction is carried out under a nitrogen atmosphere with a slow N2 purge. 135.2 g Freshly distilled 1-bromooctane (0.70 mole, fw=221.19, ˜121 mL) is added to the stirring mixture in a dropwise fashion at such a rate that the reaction exotherm maintains the reaction temperature in the range 55-65° C. Under these conditions, the bromooctane addition requires about 2 hours. After the entire bromodecane is added and the reaction temperature drops below 45° C., the stirring reaction mixture is heated to 80° C. for 2 hr and then allowed cool. The reaction mixture is periodically monitored by HPLC in order to ensure that the bromooctane is entirely consumed. As the reaction cools, a less dense upper layer of the product begins to form. Upon cooling as the reaction to ambient temperature, 100 mL distilled water is added portionwise to the stirring mixture in order to facilitate phase separation and prevent crystallization of amine hydrobromide. The reaction mixture is transferred to a 1 L separatory funnel and them cooled to about −20° C. for 2 hours in order to achieve full phase separation. The lower phase is discarded and the upper phase is retained in the funnel. 1.0 L 10% w/w NaOH in distilled water is added, the mixture is thoroughly mixed and then allowed to settle for about 1 hour. The phases are again separated, the upper product phase is retained, 1.0 L distilled water is added to the mixture that is through mixed. The phases are separated after about 2 hours, and the upper product phase is placed in a rotary evaporator (80° C. bath temp.) in order to remove water, acetonitrile and some residual starting amine. This procedure yields 143 g (88%) of a pale yellow viscous liquid with a purity of 96-98% (GC, HPLC). The major impurity is the starting amine (2-4%). This material is vacuum distilled (172-175° C., 1 torr) giving a 90% distillation yield of a colorless liquid (99.8% purity). This is a clean reaction that produces good quality product if the starting secondary amine and primary alkyl halide are themselves pure.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1[NH:25]C2C=CC=C3C(=O)NCCC=1C=23>>[NH2:25][C:5]1[CH:6]=[C:1]([C:7]#[C:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2c(I)[nH]c3cccc1c23
Reactant: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Product: Nc1cccc(C#Cc2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described for Example N, Compound 17, 3-ethynyl-analine (129 mg, 1.10 mmol) was coupled to 2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (312 mmol, 1.00 mmol) to yield 2-(3-amino-phenylethynyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 250 mg (83%) as a pale yellow solid: m.p. 261-262° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.00 (m, 2H), 3.45 (m, 2H), 5.31 (br s, 2H), 6.63 (m, 1H), 6.71 (m, 1H), 6.76 (m, 1H), 7.08 (app t, J=7.8 Hz, 1H), 7.26 (app t, J=7.8 Hz, 1H), 7.48 (dd, J=8.1, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 8.09 (br t, 1H), 11.75 (br s, 1H). MS (electrospray, MH+) 302. Anal. (C19H15N3O.0.15 H2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=2[S:8][CH:9]=1
Reactant: Cc1cccc2ccsc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c(Br)csc12
Yield: 10 %

Procedure:
25 g of 7-methylbenzo[b]thiophene are dissolved in chloroform and 27 g of bromine added at room temperature with stirring. After one hour the mixture is poured onto water and the organic phase separated, washed, dried and concentrated under vacuum. The title compound (contaminated with ca. 10% of 4-bromo-7-methylbenzo[b]thiophene) is obtained as an oil following vacuum distillation at 92°-98°/2.6 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:29]=[CH2:30])[C@H:9]([N:17]([CH:22]([CH:26]2[CH2:28][CH2:27]2)[CH:23]2[CH2:25][CH2:24]2)[C:18](=[O:21])C=C)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:17]([CH:22]([CH:26]3[CH2:27][CH2:28]3)[CH:23]3[CH2:24][CH2:25]3)[C:18](=[O:21])[CH:30]=[CH:29]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)N(C(C1CC1)C1CC1)[C@H](c1ccc(Cl)cc1)[C@H](C=C)c1cccc(Cl)c1
Solvent: ClCCCl
Product: O=C1C=C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C(C1CC1)C1CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 2.1 g (4.77 mmol) of N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-N-(dicyclopropylmethyl)acrylamide (Example 115, Step G) in 50 mL of DCE was added 160 mg of 1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexylphosphine)ruthenium (“Grubb's 2nd Generation Catalyst”). The resulting mixture was degassed two times and then heated to 70° C. for 18 h. Another 160 mg of Grubb's 2nd Generation Catalyst was added at that time and heating was continued for another 18 h. The reaction mixture was cooled to room temperature. The solvent was removed and the residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 90/10 to 20/80) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:18][CH2:19][N:14]([CH2:12][CH2:11][CH:9]2[CH2:8][CH2:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH2:10]2)[CH2:15][CH2:16]1
Reactant: Nc1nc2c(s1)CC(CC(=O)N1CCN(c3ccccn3)CC1)CC2
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1nc2c(s1)CC(CCN1CCN(c3ccccn3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of (+)-1-[(2-amino-4,5,6,7-tetrahydro-6-benzothiazolyl)acetyl]-4-(2-pyridyl)piperazine (2.70 g) (Example M) in 250 ml of tetrahydrofuran is added sodium borohydride (1.07 g) under nitrogen. This suspension is cooled in an ice bath and boron trifluoride etherate (4.6 ml) added dropwise. The mixture is stirred at room temperature for one hour and the solvent removed in vacuo. The residue is dissolved in 250 ml of a 10% solution of hydrochloric acid and stirred for two hours. The solution is made basic with ammonium hydroxide and extracted with chloroform (2×200 ml). The combined chloroform extracts are dried (magnesium sulfate), filtered, and concentrated. The residue is purified by MPLC (silica; 5% methanol, 95% chloroform) to give 1.74 g of (+)-4,5,6,7-tetrahydro-6-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-2-benzothiazolamine, containing one-fourth of a molecule of water, as a colorless solid; mp 176°-190° C.; [α]D =+52.2° (c=1.02; 0.1 N hydrochloric acid solution).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([O:21]COC)[CH2:11][C@@H:10]4[CH3:25])[CH2:7][CH2:6][C:5]=2[CH:4]=1.Cl.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][C@@H:10]4[CH3:25])[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COCO[C@H]1C[C@H](C)[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]3[C@@H](C)C[C@H](O)[C@@]3(C)CC[C@H]21
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
A solution of 9 mg (0.026 mmol) of 59, 5 μL of concentrated HCl, in MeOH (2 mL) was stirred at rt for 15 min then heated at 60° C. for 30 min. Another 25 mL of concentrated HCl was added and the reaction was stirred at 60° C. for 1 h. The reaction mixture was poured into saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (3×, 5 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a clear yellow oil. Purification by flash chromatography on 2×17 cm column of silica gel using 2:1 hexanes/EtOAc as eluent gave 7.3 mg (93%) of 6025. Data for 60: TLC, T-1, Rf 0.31; 1H NMR (400 MHz, CDCl3) δ 0.82 (s, 3H, H-18), 0.90 (t, 1H, J=10.2 Hz, H-14) 1.13 (d, 3H, J=6.3 Hz, 15α-CH3), 3.76 (t, 1H, J=8.7 Hz, H-17α), 3.79 (s, 3H, ArOCH3), 6.63 (d, 1H, J=2.7 Hz, H-4), 6.72 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.22 (d, 1H, J=8.6 Hz, H-1).
Reaction SMILES: [Li].[H-].[NH2:3][C:4]1[N:9]=[C:8]([CH2:10][C:11](OCC)=[O:12])[CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCCC1.O>[NH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1cccc(N)n1
Agent: [H-]
Agent: [Li]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(CCO)n1
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
Lithium alumnium hydride (114 mg) was dissolved in tetrahydrofuran (10 ml). To the solution was added dropwise, at 0° C., a solution of ethyl 2-(6-amino-2-pyridyl)acetate (0.54 g) in tetrahydrofuran (4 ml). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture were added water (0.12 ml) and 1N sodium hydroxide (0.36 ml), successively. Resulting insolubles were filtered off, and the filtrate was concentrated. The concentrate was purified by means of a column chromatography (carrier: silica gel, 30 g, developing solvent: ethyl acetate-acetone, 4:1) to afford the title compound (0.23 g) as an oily product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCOCC5)cc4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of Intermediate 176b (0.10 mmol) and morpholine (17.4 mg, 0.200 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (31.8 mg, 0.15 mmol) and the resulting yellow solution stirred at RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was extracted with DCM (3 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a vivid yellow gum. Flash chromatography (silica 12 g, 3.5-4.5% (2M NH3 in MeOH) in DCM) gave a vivid yellow gum (70 mg). Prep HPLC (Gemini C18, 25-75% MeCN in water, 0.1% HCO2H, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was extracted with DCM (3×15 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave a glassy orange solid (43.7 mg). Prep HPLC (Gemini C18, 25-50% MeCN in water, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was extracted with DCM (3×5 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave the title compound as a white solid (25.4 mg, 35%). LCMS (Method 5): Rt 3.61 min, m/z 718.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.27 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.76-1.95 (4H, m), 2.00-2.16 (2H, m), 2.37 (41-1, t, J=4.3 Hz), 2.90 (1H, ddd, J=12.1, 9.0, 3.9 Hz), 3.16 (1H, dt, J=12.2, 4.3 Hz), 3.29-3.34 (1H, m, obscured by water signal), 3.50 (2H, s), 3.56 (4H, t, J=4.5 Hz), 4.81 (1H, td, J=8.6, 5.6 Hz), 5.51 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.37 (4H, m), 7.43 (2H, d, J=8.7 Hz), 7.45 (2H, d, J=8.7 Hz), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, dd, J=2.2, 0.9 Hz), 8.08 (1H, s).