Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C(=O)C.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromo-ethyl)-4-nitro-benzene (0.740 g, 3.22 mmol), morpholine (0.840 mL, 9.65 mmol), and sodium iodide (0.480 g, 3.22 mmol) in N,N-dimethylacetamide (3 mL) was heated at 80° C. for 10 min. The mixture was diluted with 30 mL EtOAc and washed with H2O (2×30 mL) and brine (30 mL) and dried over Na2SO4 to give the title compound as a yellow oil of sufficient purity to use in the next step. Mass spectrum (ESI, m/z): Calcd. for C12H16N2O3, 237.1 (M+H). found 237.2.
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:12][P+:13]([CH2:18]O)([CH2:16]O)[CH2:14]O.[CH3:20][NH:21][C:22]([NH:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]([CH2:18][P+:13]([CH2:12][N:21]([CH3:20])[C:22]([NH:24][CH3:25])=[O:23])([CH2:14][N:21]([CH3:20])[C:22]([NH:24][CH3:25])=[O:23])[CH2:16][N:21]([CH3:20])[C:22]([NH:24][CH3:25])=[O:23])[C:22]([NH:24][CH3:25])=[O:23]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: O=S(=O)([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 73.9 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium benzenesulfonate (15.61 g, 0.05 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (200 ml), following Example 1, gave 21.91 g (73.9%) of tetrakis(1,3-dimethylureidomethyl)phosphonium benzenesulfonate (I, R=R'=CH3, R"=H, X=SO3C6H5) as a white, crystalline solid, mp 103°-105° C. after three recrystallizations from acetonitrile (3 ml/g). The analytical sample, dried under vacuum for 4 hr at 56° C. (acetone), analyzed as a hydrate.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=CC(C2C=CC([C:31]#[N:32])=CC=2)=CC=1.O1C=CC(B(O)O)=C1>CO>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][C:15]([C:31]#[N:32])=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)=[CH:8]1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: OB(O)c1ccoc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Yield: 53 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, crude 4'-bromo-biphenyl-4-carbonitrile (200 mg, 0.775 mmol) and 3-furanboronic acid (see Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243; 105 mg, 0.937 mmol) in MeOH (2 mL) were coupled to give a yellow solid, which was purified via preparative TLC. Elution with EtOAc:benzene (1:99) provided 100 mg (53%) of 4'-furan-3-yl-biphenyl-4-carbonitrile as a grey powder, mp 199-203° C. 1H NMR (CDCl3): δ 7.81 (bs, 1H), 7.72 (d, 4H, J=1.9 Hz), 7.61 (s, 4H), 7.51 (bs, 1H), 6.75 (s, 1H). IR (KBr): 2225, 1604, 1503, 1396, 1162, 1102, 1058 cm-1. Anal. Calculated for C17H11NO.0.3 EtOAc.0.2 C6H6 : C, 80.78; H, 5.05; N, 5.01. Found: C, 80.96; H, 4.88; N, 5.00.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.Cl[S:25]([N:28]=C=O)(=[O:27])=[O:26]>O>[S:25](=[O:27])(=[O:26])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:28]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 54.4 %

Procedure:
A mixture composed of 215 mg of 2′-nitrobiphenyl-4-ol and 1 ml of toluene was cooled with ice, and 148 mg of chlorosulfonyl isocyanate was added dropwise thereto, followed by refluxing for 17 hours. After water was added to the reaction mixture under cooling with ice, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 160 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: [CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([N:24]=[C:25]=[S:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1.N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([NH:24][C:25]([NH:33][CH2:34][CH2:35][C:36]3[N:40]=[CH:39][NH:38][CH:37]=3)=[S:26])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)N=C=S)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=S)NCCc2c[nH]cn2)CC1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To 400 mg (0.87 mmol) of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxy-phenyl)propionyl]piperidine-4-carboxylate in 5 mL of DMF are added 97 mg (0.87 mmol) of histamine and then 0.130 mL (0.87 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction medium is stirred for 2 hours and then hydrolysed by adding aqueous 5% citric acid solution. The organic compounds are extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 80/20 CH2Cl2/MeOH). 265 mg of ethyl 4-cyclohexyl-1-[(R)-2-{3-[2-(1H-imidazol-4-yl)ethyl]thioureido}-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a pale yellow powder are obtained in a yield of 53%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH3:17])[C:6]=2[N:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:35][NH2:36])=[O:34]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][NH:35][C:33]([C:29]2[O:28][CH:32]=[CH:31][CH:30]=2)=[O:34])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH3:17])[CH3:26])[C:6]=2[N:7]=1
Reactant: CN(CCN(C)c1ccc(F)cc1F)CCn1ccc2c(Cl)nc(N)nc21
Reactant: NNC(=O)c1ccco1
Solvent: CN1CCCC1=O
Product: CN(CCN(C)c1ccc(F)cc1F)CCn1ccc2c(NNC(=O)c3ccco3)nc(N)nc21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The title B compound, N1-(2-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-N2-(2,4-difluorophenyl)-N1,N2-dimethylethane-1,2-diamine (196.8 mg, 0.50 mmol) and 2-furoic hydrazide (126.0 mg, 1.0 mmol) are dissolved in 2.0 mL of NMP. The solution is stirred at 150.0° C. for 3 h before it is cooled down to RT. The solvent is removed to afford N′-(2-amino-7-(2-((2-((2,4-difluorophenyl)(methyl)amino)ethyl)(methyl)amino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide. LC/MS showed product as one peak.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH2:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:29]=[C:28]2I.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:29]=[C:28]2[NH:23][C:8]1[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:15][C:10]=2[N:9]=1
Reactant: Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CN4CCCCC4)ccc3n2C2CCCCC2)c2cc(Br)ccc21
Yield: 68.1 %

Procedure:
A mixture of 1-cyclohexyl-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-amine (420 mg, 0.00134 mol), 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (916 mg, 0.00202 mol), xantphos (237 mg, 0.000410 mol), tris(dibenzylideneacetone)dipalladium(0) (147 mg, 0.000160 mol), and potassium phosphate (510 mg, 0.00240 mol) in 1,4-Dioxane (6.0 mL) was flushed with argon. The mixture was microwaved at 300 watts, 130° C. for 15 minutes. The reaction mixture was filtered, concentrated and purified by preparative HPLC to yield 582 mg of 5-bromo-N-(1-cyclohexyl-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine as the bis-TFA salt.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][O:17][C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:33][C:34]2[S:35][C:36]([CH3:39])=[N:37][N:38]=2)C(=O)OC(C)(C)C)[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([O:5][CH:6]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)[CH:7]1[CH2:16][O:17][C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][CH2:33][C:34]2[S:35][C:36]([CH3:39])=[N:37][N:38]=2)[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C2C(COc3cc(N(Cc4nnc(C)s4)C(=O)OC(C)(C)C)nc(C)n3)C2OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2C(COc3cc(NCc4nnc(C)s4)nc(C)n3)C2OC(C)(C)C)nc1
Yield: 65.4 %

Procedure:
The solution of 12-7 (41 mg, 0.074 mmol) in TFA (0.5 mL) was stirred for 1 h at rt. The excess TFA was removed under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and adjusted to pH=9-10 with saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc, dried over sodium sulfate, concentrated under reduced pressure and purified by reverse phase column (Waters Sunfire Prep C18 OBD, 5-95% methanol in water with 0.1% NH3H2O modifier). The product was obtained as a white solid (22 mg, 65%). 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.51 (s, 1H), 7.12 (d, J=4.8 Hz, 1H), 5.63 (s, 1H), 5.43 (s, 1H), 4.91 (d, J=6.3 Hz, 2H), 4.36 (d, J=6.8 Hz, 2H), 3.66 (s, 1H), 2.73 (s, 3H), 2.47 (s, 3H), 2.33 (m, 4H), 2.03 (m, 1H), 1.06 (s, 9H); LRMS (ES) calculated M+H for C23H31N6O2S: 455.6. Found:455.2.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2cn[nH]c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gives the compound “A34”;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])[CH:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[C:5]([O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([CH3:26])[CH2:6][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccccc1)C(O)c1ccc(OCc2ccccc2)c2ccccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)c2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4Benzyloxynaphthalen-1-yl)-2-phenoxy-3-hydroxy-2-methylpropionic acid ethyl ester (1.80 g, 3.9 mmol) in anhydrous CH2Cl2 (20 mL) was cooled to 0° C. and treated with BF3-Et2O (0.48 mL, 3.9 mmol, d=1.154) and triethylsilane (0.63 mL, 3.9 mmol, d=0.728). The mixture was stirred for 2 hr, gradually warming to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously for 15 min. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to 3-(4-benzyloxynaphthalen-1-yl)-2-phenoxy-2-methylpropionic acid ethyl ester as a golden oil (1.55 g, 89%). Rf=0.41 (9:1 hexanes:ethyl acetate). 1H NMR (300 MHz, CDCl3): δ 8.33 (d, 1H, J=8.3), 8.11 (d, 1H, J=8.3), 7.47 (d, 2H, J=7.8), 7.40 (t, 1H, J=8.3), 7.37 (t, 1H, J=8.3), 7.36 (t, 2H, J=7.8) 7.28 (d, 2H, J=7.8), 7.11 (t, 2H, J=8.8), 6.87 (t, 1H, J=7.8), 6.79 (d, 1H, J=7.8), 6.69 (d, 2H, J=8.8), 5.18 (s, 2H, 4.08 (q, 2H, J=7.0), 3.66 (d, 1H, J=14.4), 3.54 (d, 1H, J=14.4), 1.38 (s, 3H), 1.13 (t, 3H, J=7.0). MS [EI+] 458 (M+NH4)+
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][C:29](=[O:31])[CH3:30])[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
Prepared using General Procedure 14: To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 50 (500 mg, 1.26 mmol) in DCM (5 mL) was added TEA (527 μL, 378 mmol). The reaction was cooled to 0° C. and acetyl chloride (135 μL, 1.89 mmol) was added. The reaction was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was diluted with DCM (100 mL) and washed successively with saturated NH4Cl and NaHCO3. The organic layers were dried over MgSO4, filtered and concentrated to crude product. The crude product was recrystallized from hot ethanol (75 mL) to afford 420 mg (83%) of (S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide 139 as off-white crystals. LCMS-ESI (m/z) calculated for C23H22N4O3: 402.2; found 403.1 [M+H]+, tR=8.77 min (Method 2). Elemental Analysis determined for C23H22N4O3; C calculated=68.64%; found=68.54%. H calculated=5.51%; found=5.36%. N calculated=13.92%; found=13.85%. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=2.2 Hz, 1H), 8.47 (dd, J=9.0, 2.3 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H) 8.08 (t, J=4.2 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.57-7.47 (m, 2H), 5.45-5.39 (m, 1H), 5.20-4.97 (m, 1H), 3.51-3.42 (m, 1H), 3.25-3.00 (m, 1H), 2.55-2.50 (m, 1H), 1.96 (s, 3H), 1.94-1.87 (m, 1H), 1.45 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.14, 169.85, 168.85, 162.79, 144.91, 143.26, 134.16, 133.89, 128.49, 127.40, 126.86, 123.29, 116.82, 115.29, 113.56, 103.97, 72.77, 54.56, 33.67, 31.70, 23.50, 21.75. Chiral HPLC: (S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide was eluted using 10% i-PrOH in hexanes plus 0.3% DEA: >99.9% ee, tR=15.09 min. (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide 138 was prepared in an analogous fashion from (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49: >99.9% ee, tR for (R)-enantiomer=16.44 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3]1.[ClH:15]>O1CCOCC1>[ClH:15].[ClH:15].[CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([NH2:7])[CH2:3]1
Reactant: CN1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl N-[(3R)-1-methylpyrrolidin-3-yl]carbamate (Intermediate 185; 1.18 g, 5.67 mmol) was dissolved in 1,4-dioxane (10 mL) and 4M HCl in dioxane (10 mL) added. The mixture was stirred at room temperature for 1 hour and then concentrated to yield the title compound as a white hygroscopic solid (810 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C#C)[CH2:31]CC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:30]#[CH:31])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), tributyl(ethynyl)tin (760 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in a mixture of ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100 mL). After the mixture being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.45 g of the crude product.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)/[CH:3]=[O:4].[CH:13](OC)(OC)OC>ClCCl.C(OCC)C>[CH3:13][O:4][CH:3]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([CH3:12])[CH:8]=2)[CH:5]=[C:2]1[CH3:1]
Reactant: C/C(C=O)=C\c1ccc(C)cc1
Reactant: COC(OC)OC
Solvent: CCOCC
Solvent: ClCCl
Product: COC1C(C)=Cc2ccc(C)cc21
Reaction time: 1 h
Yield: 59 %

Procedure:
Anhydrous FeCl3 (2.0 g, 12.3 mmol.) was added to a solution of (2E)-2-methyl-3-(4-methylphenyl) -2-propenal (5.0 g, 31.3 mmol.) and trimethyl orthoformate (36.4 g, 34.3 mmol.) in dichloromethane (35 ml). The dark red solution was stirred for one hour, then diluted with 100 ml of diethyl ether and washed with water (3×75 ml). The organic phase was dried (MgSO4), filtered and concentrated. Kugelrohr distillation (65-80° C., 20 mTorr) yielded 3.2 g (18.4 mmol., 59% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]1[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=1.S(Cl)([Cl:23])(=O)=O>>[Cl:23][C:14]1[C:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[N:11][N:12]([CH3:19])[C:13]=1[O:15][CH:16]([F:17])[F:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl

Procedure:
Analogously to Example 8, 35 g (114 mmol) of 3-(2,4-dichloro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were reacted with 16.9 g (125 mmol) of sulfuryl chloride. Yield: 30.8 g; 1H-NMR (270 MHz, in CDCl3): δ [ppm]=7.49 (s,1H), 7.30 (s,1H), 6.74 (t,1H), 3.85 (s,3H), 2.39 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]2[C:5]([C:6](=[O:12])[NH:7][C:8]([CH3:11])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O>[CH2:19]([N:7]1[C:6](=[O:12])[C:5]2=[CH:4][CH:3]=[C:2]([Cl:1])[N:10]2[N:9]=[C:8]1[CH3:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nn2c(Cl)ccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred mixture of 7-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.10 g, 5.99 mmol) and Cs2CO3 (2.25 g, 6.9 mmol) in dioxane (20 mL) was added benzyl bromide (0.76 mL, 6.16 mmol) and heated at 95° C. under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with water and stirred for 1 h. The precipitated solid was collected and washed with water, dried in vaccum over P2O5 at 35° C. to give the title compound (1.41 g, 87%): 1H NMR (CDCl3) δ 7.26 (m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 6.98 (d, 1H, J=4.4 Hz), 6.40 (d, 1H, J=4.4 Hz), 5.19 (s, 2H), 2.35 (s, 3H); 3C NMR (CDCl3) δ 154.0, 148.0, 135.8, 129.0, 127.8, 126.5, 117.7, 116.5, 109.7, 108.2, 45.7, 20.1; MS (ESI+) 274.04, 276.06 (M++H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reaction time: 18 h

Procedure:
Alternatively, combine 4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.7 mmol) and tetrahydrofuran (10 mL). Add a solution of lithium aluminum hydride in tetrahydrofuran (2.7 mL, 1 M, 2.7 mmol). After 18 hour, quench by slow portionwise addition of Glauber's salt (Na2SO4.10 H2O) until gas evolution ceases. Add dichloromethane (20 mL) and celite and stir. Filter and evaporate in vacuo to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)[C:11](=[O:20])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[OH-].[OH-].[Pd+2]>[CH:16]1([CH2:15][N:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]2=[O:20])[CH2:17][CH2:18][CH2:19]1
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CCC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1cc(O)ccn1CC1CCC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A solution of the product of Example 468A (0.426 g, 1.58 mmol) in tetrahydrofuran (20 mL) was treated with ammonium formate (0.38 g, 6.03 mmol) and a catalytic amount of 20% palladium hydroxide on carbon at 70° C. for 2 hours. The reaction mixture was cooled to about 25° C., filtered through diatomaceous earth and the filtrate concentrated under reduced pressure to provide the title compound (0.244 g, 86%).