Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1>C1(C)C=CC=CC=1.CN(C=O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCNC2CCCC2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@@H]3CCC[C@H]3O)cc2)nc1
Yield: 18.2 %

Procedure:
Heat a mixture of 4-[2-(2-hydroxycyclopentylamino)ethyl]phenol (210.5 mg, 0.95 mmol), K2CO3 (395 mg, 2.85 mmol) and 6-chloronicotinamide (223.4 mg, 1.43 mmol) in 1:3 toluene/DMF (6 mL) at 165° C. for 2 hours, while removing H2O azeotropically with toluene. Remove DMF azeotropically with xylenes and take up the residue in H2O (50 mL) and 10% MeOH in CH2Cl2 (50 mL). Shake and separate the layers. Extract the aqueous layer with 10% MeOH in CH2Cl2 (2×50 mL) and 10% MeOH in EtOAc (50 mL). Combine the organic layers, dry over MgSO4 and concentrate. Concentrate the aqueous layer, which still contains the product by TLC, to dryness and extract the product out with MeOH. Dry the solution with Na2SO4, filter and combine with the organic concentrate above. Concentrate, re-dissolve in MeOH and filter through a Na2SO4 pad. Concentrate and purify by flash chromatography, eluting with 10:15:75 2.0 M NH3 in MeOH/CH2CL2/EtOAc to afford the title compound (137.4 mg) along with the (cis)-isomer of the starting phenol (59.0 mg) recovered: MS ES+ 342.0 (M+H)+, HRMS calcd for C19H24N3O3 342.1818 (M+H)+, found 342.1812, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=16.76 min, 100% purity; Anal. Calcd for C19H23N3O30.1CH2Cl2 0.1EtOAc: C, 65.29; H, 6.74; N, 11.71. Found: C, 65.35; H, 6.61; N, 11.98.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[S:12]([O-:15])([O-:14])=[O:13].[Na+].[Na+].O>C(O)C>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[S:12]([OH:15])(=[O:14])=[O:13]
Reactant: Cc1ccc(C(=O)O)nc1Cl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)O)nc1S(=O)(=O)O
Temperature: 180 °C
Yield: 111.2 %

Procedure:
6-chloro-5-methyl-pyridine-2-carboxylic acid (0.85 g, 4.97 mmol) and sodium sulfite (CAN 7757-83-7, 1.5 g, 11.9 mmol) were added to water (3 mL) and ethanol (3 mL). The mixture was heated to 180° C. for 4 h in a sealed tube. After that the mixture was cooled to room temperature and a solid precipitated that was removed by filtration. The filtrate was concentrated and added to water (20 mL). The aqueous phase was washed with ethyl acetate (2×20 mL). Subsequently the aqueous phase was adjusted to pH=2 with 2 N hydrochloric acid. Water was removed in vacuo to give the product as solid (1.2 g); MS (EI): m/e=218.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc2oc3ccccc3c2c1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc3oc4ccccc4c3c2)c1

Procedure:
Acid (18) (50 mg, 0.24 mmol) was coupled to aniline (2) (54 mg, 0.28 mmol) using Method D, except that DMF (1 mL) was used. The product was further purified by trituration in DCM/heptane to give the title compound. Yield: 46 mg, 51%; LC-MS tr 1.70 min; HPLC Purity: 97-100%; MS (ES+) m/z 386 (M+H)
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and commercially available 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (36 mg, 28%). MS (ISP) 483.5 [(M+H)+]; mp 262–264° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:29][C:30](=[O:32])[CH3:31])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1F.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:30]([NH:29][C:24]1[CH:23]=[C:22]([N:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][C:25]=1[F:28])(=[O:32])[CH3:31]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(NC(C)=O)c2)s1
Agent: CC(=O)Nc1ccc(F)c(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(=O)Nc1cc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)ccc1F

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-4-fluoro-phenyl)-acetamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:15](=[O:30])[CH2:16][N:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]([C:26]([F:29])([F:28])[F:27])=[N:18]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:32]([N:3]1[CH:4]=[CH:5][N:1]=[C:2]1[C@@H:6]([NH:14][C:15](=[O:30])[CH2:16][N:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]([C:26]([F:27])([F:28])[F:29])=[N:18]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reactant: CC(C)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)CCn1ccnc1[C@H](Cc1ccccc1)NC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 90 °C
Reaction time: 15 h

Procedure:
(S)-N-(1-(1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (42 mg, 0.1 mmol) and 1-bromo-3-methylbutane (24 μL, 0.2 mmol) were combined in DMF (0.6 mL) and treated with K2CO3 (21 mg, 0.15 mmol) and TBAI (4 mg). The reaction was heated to 90° C. and stirred for 15 h. The reaction was purified by RP HPLC to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 7.23 (q, 7.5 Hz, 3H), 7.16-7.09 (m, 2H), 5.24 (m, 1H), 4.75 (s, 2H), 3.83 (m, 3H), 3.22 (d, 1H), 2.35 (m, 2H), 1.63 (m, 5H), 1.40 (m, 2H), 0.77 (t, 6H). MS (m/z) 488.5 [M+H]+.
Reaction SMILES: C[N:2]([CH2:4][C:5]1OC(CSCCN)=C[CH:6]=1)C.C(C=C(OC)OC)#N.[C:23]([CH:25]=[C:26](OC)[NH:27][CH2:28][CH2:29][S:30][CH2:31][C:32]1[O:33][C:34]([CH2:37][N:38]([CH3:40])[CH3:39])=[CH:35][CH:36]=1)#[N:24].C(N)C#C>>[C:23]([CH:25]=[C:26]([NH:2][CH2:4][C:5]#[CH:6])[NH:27][CH2:28][CH2:29][S:30][CH2:31][C:32]1[O:33][C:34]([CH2:37][N:38]([CH3:40])[CH3:39])=[CH:35][CH:36]=1)#[N:24]
Reactant: COC(=CC#N)NCCSCc1ccc(CN(C)C)o1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: C#CCN
Agent: COC(=CC#N)OC
Product: C#CCNC(=CC#N)NCCSCc1ccc(CN(C)C)o1

Procedure:
Alternatively, when 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene and the resultant 1-cyano-2-methoxy-2-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}ethylene is reacted with propargylamine according to the general procedure of Example 1, the title product is produced.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21].[Li]CCCC.[B:27](OC)([O:30]C)[O:28]C.O>C1COCC1>[CH3:21][O:20][C:11]1[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH2:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:27]([OH:30])[OH:28]
Reactant: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(CSc2ccccc2B(O)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 46 %

Procedure:
To a solution of 4.22 g (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (11.56 mmol) in 150 ml dry THF at −78° C. was added slowly 5.6 ml 2.5M n-BuLi. The solution was stirred at −78° C. for 25 minutes. 1.6 ml B(OMe)3 was added at −78° C. The reaction was stirred 2 hours at RT. 100 ml water was added, stirred overnight. The mixture was extracted with ethyl acetate (2×100 ml). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by gradient chromatography (hexane:ethyl acetate 60:40) yielded 1.762 g product (5.3 mmol, 46% yield).
Reaction SMILES: [C:1]1([CH2:17][OH:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>CN(C=O)C.ClCCl>[Br:19][CH2:20][C:21]([O:18][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CBr)OCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 23 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
Pyrenemethanol (Pyr-OH) (109.6 mg, 0.47 mmol) in 1.0 mL DMF (anh) was treated with 180 μL TEA (anh, 1.29 mmol) and 2-bromoacetyl bromide (132.2 μL, 1.50 mmol) in 1 mL dichloromethane. The mixture was stirred at RT (˜23° C.) for 17 hours. After the solvent was evaporated, the crude product was purified by silica gel column (Hex/EtOAc=2/1) to give 167 mg final product as a yellow solid (yield 90%). 1H NMR (CDCl3, 500 MHz): δ 8.28-8.03 (m, 9H, ArH), 5.94 (s, 2H, ArCH2), 3.90 (s, 2H, CH2Br). ESI: 375, [M+Na]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([OH:15])=[C:7]([C:16](OCC)=[O:17])[C:6]2=[O:21])[CH2:3][CH2:2]1.[C:22]([NH:35][NH2:36])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([OH:15])=[C:7]([C:16]([NH:36][NH:35][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:17])[C:6]2=[O:21])[CH2:3][CH2:2]1
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC2CC2)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccccc2n(CC2CC2)c1=O

Procedure:
Reagents: Comp 31 (0.45 mmols, 0.13 g); dodecanoyl hydrazine (0.68 mmols, 0.15 g). Yield: 0.09 g (49%), white solid, m.p.=121° C.-122° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)S(O[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][C@H:22]([N:29]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][O:24]2)(=O)=O>>[CH2:37]([N:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:22]1[CH2:21][C:20]2[C:25](=[CH:26][CH:27]=[CH:28][C:19]=2[C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[O:24][CH2:23]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ncc(B(O)O)cc1F
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: COc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cc1F
Yield: 71 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 71% yield, starting from 5-fluoro-6-methoxypyridin-3-ylboronic acid (1.7 equiv) and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (1 equiv): 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, 1 H), 7.73 (dd, 1 H), 7.23-7.37 (m, 8 H), 7.06-7.22 (m, 3 H), 6.78 (dd, 2 H), 4.34 (d, 1 H), 3.92-4.08 (m, 4 H), 3.60-3.79 (m, 4 H), 3.18-3.30 (m, 1 H), 2.89-3.10 (m, 2 H); MS (ESI) m/z 455[M+H+].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH:10]([F:12])[F:11])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH2:23])=[N:19][CH:20]=1>>[F:11][CH:10]([F:12])[O:9][C:4]1[CH:3]=[C:2]([NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:25])([F:13])[F:24])=[CH:20][N:19]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(I)cc1OC(F)F
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1OC(F)F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-difluoromethoxy-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 347.1 [M+H]+) was prepared from 4-iodo-2-difluoromethoxy-toluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:30])([F:29])[F:31])[C:9]=4[CH:17]=3)[CH:19]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.9 (M+H+); retention time=0.99 minutes.
Reaction SMILES: C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:10]1([C:16]2[N:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][OH:25])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C.[I:32][C:33]1[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[I:32][C:33]1[CH:38]=[CH:37][C:36](/[C:22](/[C:19]2[CH:20]=[N:21][C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:17][CH:18]=2)=[CH:23]\[CH2:24][OH:25])=[CH:35][CH:34]=1
Reactant: OCC#Cc1ccc(-c2ccccc2)nc1
Reactant: Ic1ccc(I)cc1
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C(\c1ccc(I)cc1)c1ccc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium methoxide (2.5 mg, 0.045 mmol) was added to 1 M solution of lithium aluminum hydride in tetrahydrofuran (1.43 mL, 1.43 mmol). The mixture was cooled to 0° C. and a solution of 3-(6-phenylpyridin-3-yl)prop-2-yn-1-ol (300 mg, 1.43 mmol) in tetrahydrofuran (6 mL) was slowly added. The reaction mixture was stirred at 0° C. for 2 h and then at ambient temperature for 2 h. The reaction mixture was cooled to 0° C. again, ethyl acetate (0.24 mL, 2.4 mmol) was added and the mixture was stirred for further 10 min without cooling. 1,4-Diiodobenzene (527 mg, 1.60 mmol), anhydrous zinc chloride (108 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (29.5 mg, 0.029 mmol) and tri-(2-furyl)phosphine (26.6 mg, 0.118 mmol) were added, the mixture was degassed and kept under argon. The mixture was heated at 60° C. for 20 h; methanol (0.7 mL) was added and the mixture was stirred for additional 1 h. The reaction mixture was diluted with ether (30 mL) and subsequently saturated aqueous solution of ammonium chloride (0.36 mL) was added. The formed suspension was filtered through a paddle of silica gel and the paddle was thoroughly washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) affording (E)-3-(4-iodophenyl)-3-(6-phenylpyridin-3-yl)prop-2-en-1-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 90 °C

Procedure:
30 g (0.127 mol) of 2,5-dibromopyridine in suspension in 100 ml of toluene, 15.4 g (0.127 mol) of phenylboronic acid, 4.4 g (0.0038 mol) of tetrakis(triphenylphosphine)palladium, 90 ml of a 2M aqueous solution of sodium carbonate and 4 ml of ethanol are introduced in succession into a 500 ml three-necked flask, and the mixture is heated at 90° C. for 22 h.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([C:1]([NH:27][NH2:28])=[NH:2])[N:4]=[C:5]2[NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(F)cc23)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(F)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (350 mg, 1 mmol) in MeOH (10 mL) was added NH2NH2—H2O (10 mL). The reaction mixture was heated to reflux for 2 hours. The solvent was removed to give the title compound as white solid, which was used without further purification (350 mg, 92%). ESI-MS m/z [M+H]+ 389.2.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][CH:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:22])[N:19]([CH3:21])[CH2:20][C:14]=2[CH:13]=1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CC(O)=O>[NH2:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][CH:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:18](=[O:22])[N:19]([CH3:21])[CH2:20][C:14]=2[CH:13]=1
Reactant: COC(=O)CC1Cc2ccc(NC(=O)OCc3ccccc3)cc2CN(C)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CC1Cc2ccc(N)cc2CN(C)C1=O
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
A mixture of methyl (±)-8-[(benzyloxycarbonyl)amino]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (1.5 g), Pearlman's catalyst (0.30 g), and warm AcOH (300 mL) was stirred under H2 (balloon pressure). After 90 min, the mixture was filtered to remove the catalyst, and the filtrate was concentrated to give the title compound as a viscous oil (1 g, 100%): 1H NMR (CDCl3) δ7.00 (br s, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.57 (dd, J=8.1, 2.3 Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.25 (d, J=16.3 Hz, 1H), 3.78 (m, 1H), 3.70 (s, 3H), 3.68 (d, J=16.3 Hz, 1H), 3.03 (s, 3H), 3.00-2.80 (m, 3H), 2.40 (dd, J=16.7, 5.3 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=O)(C)(C)C.[S:16](N)(N)(=[O:18])=[O:17]>N1C=CC=CC=1>[S:16]1(=[O:18])(=[O:17])[N:11]2[CH:10]([CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:14][NH:15]1
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCNC(CN)C1
Solvent: c1ccncc1
Product: O=S1(=O)NCC2CNCCN21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-aminomethyl-piperazine-1-carboxylic acid tert-butyl ester (CAS number: 1376099-80-7, Bepharm) (215 mg, 1.0 mmol) in 2 mL of pyridine was added sulfamide (1.5 mmol). The reaction mixture was heated to 150° C. for 6 hours under microwave. The solvent was removed in vacuo, and the residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. The reaction mixture was stirred for 1 hour, and the solvent was removed in vacuo to give the crude Compound P which was used directly without further purification. LC/MS: calc'd 178 (MH+), measured 178 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:10]=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[N:13]=2)=[CH:4][C:3]=1[CH3:19].[F:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]2[C:29]=1[C@H:28]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:27][CH2:26]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C:9]3[N:10]=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[N:13]=3)=[CH:4][C:3]=2[CH3:19])=[C:25]2[C:29]=1[C@H:28]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:27][CH2:26]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nnn(C(C)(C)CO)n2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn(C(C)(C)CO)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 2-(5-(4-bromo-3,5-dimethylphenyl)-2H-tetrazol-2-yl)-2-methylpropan-1-ol and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.25 min; Mass spectrum (ESI+): m/z=587 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: OC1(c2ccc(Br)cc2C(F)(F)F)CCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(Br)ccc1C1CCC1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution in chloroform (10.0 mL) of the compound (1.00 g) obtained in step (1) above and triethylsilane (406 mg), a solution of boron trifluoride/diethyl ether complex (601 mg) in chloroform (4.00 mL) was added at −65° C. After being brought to 0° C., the mixture was stirred at that temperature for 30 minutes. Subsequently, potassium carbonate (1.08 g) and water (10.0 mL) were added and the mixture was brought to room temperature. After phase separation, the organic layer was dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-90:10) and further purified by NH silica gel column chromatography (n-hexane) to give 4-bromo-1-cyclobutyl-2-(trifluoromethyl)benzene as a colorless oil (490 mg).