Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]2=[O:27])=[C:17]([F:30])[CH:16]=1.[CH3:31][S-:32].[Na+]>CN(C=O)C.ClCCl>[CH:12]1([CH2:11][N:7]2[C:6]3[CH:5]=[CH:4][C:3]([C:15]4[CH:29]=[CH:28][C:18]([CH2:19][N:20]5[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]5=[O:27])=[C:17]([F:30])[CH:16]=4)=[C:2]([S:32][CH3:31])[C:10]=3[N:9]=[N:8]2)[CH2:14][CH2:13]1
Reactant: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Br)cc2F)C1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1c(-c2ccc(CN3CC(=O)N(C)C3=O)c(F)c2)ccc2c1nnn2CC1CC1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
To a solution of 1-{4-[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]-2-fluorobenzyl}-3-methylimidazolidine-2,4-dione (10 mg, 0.021 mmol) in DMF (0.18 mL) was added sodium thiomethoxide (5.6 mg, 0.080 mmol, 4 equiv.). The mixture was stirred at 120° C. for 3.5 hours, cooled to ambient temperature and diluted with dichloromethane, which was washed with water and brine. The organic extract was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound: 1H NMR (400 MHz, CDCl3) 7.39-7.45 (m, 2H), 7.34 (d, 1H, J=8.4 Hz), 7.18-7.24 (m, 2H), 4.70 (s, 2H), 4.53 (d, 2H, J=7.1 Hz), 3.90 (s, 2H), 3.06 (s, 3H), 2.85 (s, 3H), 1.40-1.46 (m, 1H), 0.67-0.71 (m, 2H), 0.50-0.54 (m, 2H) ppm. LRMS m/z (M+H) 440.2 found, 440.1 required.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]#[CH:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][C:24]#[CH:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon was added 0.6 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 1.38 ml of propargyl bromide was added. This mixture was stirred for 12 hours then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3) as the eluent. Fractions containing the desired product were collected, evaporated in vacuo and recrystallized from dichloromethan-hexane to give 2.5 g of orange crystals mp 195°-198° C.
Reaction SMILES: [CH3:1][C:2]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.Cl[C:29]1[CH:34]=[C:33]([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[N:32]2[N:40]=[C:41]([NH2:43])[N:42]=[C:31]2[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:43][C:41]1[N:42]=[C:31]2[CH:30]=[C:29]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:4][CH2:3][C:2]([CH3:1])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7][CH2:6]4)=[N:9][CH:10]=3)[CH:34]=[C:33]([N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)[N:32]2[N:40]=1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1nc2cc(Cl)cc(-n3cccn3)n2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(-n4cccn4)n4nc(N)nc4c3)cn2)CC1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
A suspension of ethyl 4-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-4-carboxylate (360 mg, 0.97 mmol), 7-chloro-5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (190 mg, 0.81 mmol), cesium carbonate (400 mg, 1.2 mmol) and Pd(dppf)2C12 (60 mg, 0.08 mmol) in 1,4-dioxane (4.5 mL) and water (0.5 mL) was added to a microwave vial and degassed with N2. The vessel was then heated at 110° C. in a microwave reactor for 60 mins. The resultant solution was concentrated in vacuo and the residue purified by flash column chromatography (Biotage SP4, 40 g 0-10% MeOH/DCM) and (Biotage SP4, 12 g 2% MeOH/DCM, then flush with 10% MeOH/DCM) to give the desired product as a cream solid (200 mg, 55%) MS: 448.27 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].[CH3:32][O:33][C:34](=[O:55])[C:35]1[C:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[O:49][CH2:50][CH2:51][CH2:52][CH2:53][NH2:54]>>[CH3:32][O:33][C:34](=[O:55])[C:35]1[C:40]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[O:49][CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:6](=[O:7])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Reactant: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Product: COC(=O)c1c(OCCCCNC(=O)[C@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)NC(C)=O)cccc1OCc1ccccc1

Procedure:
The title compound is prepared using (S)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid and 2-(4-aminobutoxy)-6-benzyloxybenzoic acid methyl ester (Example 110, step C) analogous to Example 131, step C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1.C(O)(=O)/C=C\C(O)=O>CN(C)C=O>[NH:25]1[CH:26]=[C:22]([CH2:21][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]#[N:10])[N:23]=[CH:24]1
Reactant: N#CC(c1ccccc1)c1ccc(Br)cc1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A 10.0 g. portion of 2-(4-bromophenyl)-2-phenylacetonitrile was mixed with 1.76 g. of 50% sodium hydride in 20 ml. of dimethylformamide, and 2.81 g. of 4-chloromethylimidazole hydrochloride in 20 ml. of dimethylformamide was added. The reaction mixture was then stirred at 100° C. for 5 hours, and at ambient temperature for 16 hours. The reaction mixture was worked up as described in Example 1 to obtain 6.1 g. of the free base of the compound named in the heading above. The compound was converted to the maleate salt by contact with maleic acid, and the salt was crystallized from diethyl ether/acetone to obtain 7.80 g. of product, m.p. 121°-124° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH:23]=1)C1C=CC=CC=1.[H][H]>C(COC)OC.CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)C(C)n1nnc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)C(C)n1nnc2ccc(O)cc21

Procedure:
A solution of methyl 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetate (31 g, 0.1 mole) in dimethoxyethane and methanol is shaken with 10% palladium on carbon catalyst (8 g, 50% water wet) under 24-33 psig of hydrogen in a Parr apparatus until approximately 0.1 mole of H2 is absorbed (21/2 hours). The reaction mixture is filtered and the filtrate is concentrated in vacuo to give the title compound as an off-white solid, 21.7 g, mp 132.5°-134.5° C., identified by NMR and elemental analyses.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.S(Cl)([Cl:29])=O.O1CCCC1>CN(C)C=O.O>[Cl:29][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.10 g), thionyl chloride (0.03 mL), N,N-dimethylformamide (1 drop) and tetrahydrofuran (6 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, aqueous sodium bicarbonate, and saturated brine in this order, dried (MgSO4) and concentrated to give the title compound (0.08 g, yield 76%) as yellow crystals. melting point 204-205° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:25]([CH3:27])[CH3:26])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:25]([CH3:26])[CH3:27])[C:16]2=[O:28])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(O)cc1
Reaction time: 1 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (215 mg) and 10% Pd—C (30.6 mg) in EtOH (10 mL) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-7-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To a solution of this solid in DMF (10 ml) were added sodium hydride (27.8 mg) and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (164 mg) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The precipitate was collected by filtration and washed with AcOEt and MeOH to give the title compound (175 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25]([NH:31][CH3:30])=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)sc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1sc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)nc1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylic acid (Example 16) (0.15 g, 0.35 mmol), methylamine (96 μL, 2.46 mmol), HATU (0.268 g, 0.70 mmol) and DIPEA (80 μL, 0.46 mmol) in DMF was stirred at 40° C. overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM (large volume). The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was twice purified by flash chromatography eluting with DCM/MeOH (95/5) to give after crystallisation from ether the title compound as a white solid (33 mg, 21%). HRMS calculated for C17H16Cl2N6O2S (M+H)+439.0511, found: 439.0548, Rt: 2.69 min. MP: 218.5° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C@H:9]([CH3:22])[C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2.O(C[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2)[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[O:1]([CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][C@H:9]([CH3:22])[C:8]1=[CH:7][C:6](=[O:23])[CH2:5][CH2:4]2)[Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO[Si](C)(C)C(C)(C)C)CCC(=O)C=C12

Procedure:
Following essentially the same procedure and substituting 19-hydroxy-6α-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 19-t-butyldimethylsiloxy-6α-methyl-4-androstene-3,17-dione.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[C:16]([CH2:18][C:19]([NH2:21])=[S:20])#[N:17]>>[NH2:21][C:19](/[C:18](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:16]#[N:17])=[S:20]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCC(N)=S
Product: CC(C)c1cc(/C=C(\C#N)C(N)=S)cc(C(C)C)c1O

Procedure:
M25 was prepared using 3,5-diisopropyl-4-hydroxybenzaldehyde and cyanothioacetamide under similar conditions as described for M11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27].[CH3:28][C:29]1(C)[C:33](C)(C)OB(C(C)=C)O1>COCCOC>[F:16][C:4]1[CH:5]=[C:6]([C:29]([CH3:33])=[CH2:28])[CH:7]=[C:2]([F:1])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:18]=1[F:27]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2F)n1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Solvent: COCCOC
Product: C=C(C)c1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 90 °C

Procedure:
To a degassed solution of methyl 6-(2,6-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)-5-fluoropicolinate (1.0 equiv.) in DME/2M Na2CO3 (3/1, 0.09 M) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.5 equiv.) and PdCl2(dppf)-CH2Cl2Adduct (0.1 equiv.). The reaction was heated to 90° C. in an oil bath for 15 min. The mixture was cooled to rt and partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography (Analogix, eluting with 0-100% ethyl acetate). The pure fractions were concentrated to yield methyl 6-(2,6-difluoro-4-(prop-1-en-2-yl)phenyl)-5-fluoropicolinate. LC/MS=308.2 (M+H), Rt=0.99 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.15 (s, 3H), 4.01 (s, 3H), 5.23 (s, 1H), 5.47 (s, 1H), 7.11 (d, J=9.39 Hz, 2H), 7.65 (t, J=8.41 Hz, 1H), 8.26 (dd, J=8.61, 3.91 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:14][CH2:12][CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: Clc1nc2cccc(Br)c2s1
Product: CCNc1nc2cccc(Br)c2s1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
7-Bromo-2-chlorobenzothiazole (100 mg, 0.40 mmol) was added to ethylamine (2.0 M in THF, 1 mL, 2 mmol) and the solution was heated at 70° C. for 1 h. The crude mixture was purified by ISCO chromatography (100% DCM) to afford 95 mg (92%) of the title compound as white solid. MS (ESI): 257.33, 259.31 [M+H]+; HPLC tR=1.27 min (HPLC: Anayltical—2 min).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(O[CH2:21][CH:22]1[CH:26]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][O:24][CH2:23]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>COCCOCCOCCOC>[CH2:1]([N:9]1[CH2:21][CH:22]2[CH2:23][O:24][CH2:25][CH:26]2[CH2:27]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COCC2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: c1ccc(CCN2CC3COCC3C2)cc1

Procedure:
Phenethylamine (0.15 mole, 18.2 grams) was reacted with a mixture of the cis and trans isomers of 3,4-bis(tosyloxymethyl)tetrahydrofuran, represented by formulas (XIX), (0.05 mole, 22.0 grams) in 60 ml triethylene glycol dimethyl ether at 185°C. for 3 hours. The reaction mixture was cooled to room temperature and neutralized with 75 ml methanolic sodium hydroxide solution (0.10 mole, 4.0 grams). After the reaction mixture was concentrated under aspirator pressure, 150 ml diethyl ether was added and sodium tosylate (18.5 grams) was filtered. Vacuum distillation of the filtrate gave 5-phenethyl-hexahydro-1H-furo(3,4-c)pyrrole (6.9 grams, b.p. 111° to 112°C./0.12 mm Hg). 5-Phenethyl-hexahydro-1H-furo(3,4-c)pyrrole was dissolved in 700 ml anhydrous diethyl ether and anhydrous hydrogen chloride was bubbled through the solution. The resulting 5-phenethyl-hexahydro-1H-furo(3,4-c)pyrrole hydrochloride was filtered, washed with ether, and dried. The product obtained had a melting point of 176° to 177°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:41])[CH2:38][C:39]#[CH:40].C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C>CN(C)C=O.C(OCC)(=O)C.[Cu]I.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[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:40]#[C:39][CH2:38][N:37]([CH3:41])[CH3:36])=[CH:10][C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2-c2ccc(Cl)cc2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[NH3+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1ccc(-c2ccc(Cl)cc2)c(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C

Procedure:
A suspension of EXAMPLE 198B (800 mg), N,N-dimethylprop-2-yn-1-amine (373 mg), copper(I) iodide (57 mg), tetrakis(triphenylphosphine)palladium(0) (259 mg), triethylamine (757 mg) and tert-butyl ammonium iodide (829 mg) in anhydrous N,N-dimethylformamide (5 mL) was heated at 100° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column purification with 0-3% methanol/dichloromethane to afford the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl.CS(Cl)(=O)=O>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCCC(O)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CCCC(OS(C)(=O)=O)C1
Reaction time: 2 h
Yield: 325.1 %

Procedure:
To a solution of 3-hydroxy-N-methyl piperidine (2 cm3, 17.4 mmol) in dichloromethane (40 cm3) was added triethylamine (3.6 cm3, 26.05 mmol) and then methanesulfonyl chloride (1.5 cm3, 19:1 mmol). The reaction was then stirred for 3 h before a further aliquot (0.2 equiv., 3.47 mmol) of methanesulfonyl chloride was added. Stirring was continued for another 2 h at room temperature before the reaction was treated with water (60 cm3) and extracted into dichloromethane (40 cm3). The organic layer was washed with saturated aqueous sodium chloride solution (60 cm3) and dried over sodium sulfate before being evaporated under reduced pressure to afford (A) (2.18 g, 11.28 mmol, 65%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]([CH:17]([CH3:25])[C:18](=[O:24])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]2[C:11]([C:12]=1[C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[CH3:3][C:4]1[N:5]([CH:17]([CH3:25])[C:18](=[O:24])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1c(C)n(C(C)C(=O)N2CCCC2)c2ccccc12
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)C(=O)N1CCCC1
Temperature: 70 °C
Reaction time: 10 h
Yield: 94.2 %

Procedure:
To a solution of sodium hydroxide solution (50 mg, 1.2 mmol) in tetrahydrofuran, menthol and water (20 mL, 3:1:1, V/V) was added methyl 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.318 mmol). The reaction mixture was stirred at 70° C. for 10 hours. The mixture was quench with 10% hydrochloric acid aqueous (2 mL), extracted with dichloromethane and menthol (60 mL, 10:1). The combine organic layer was dried by anhydrous sodium sulfate, filtered and concentrated to give 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylic acid (90 mg, 92%). LCMS (M+H+) m/z: calcd 300.15. found 300.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[N:19]=[C:20](Cl)[C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=3)[NH:23][C:22]=2[N:34]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46][NH2:47].CO>>[NH2:39][CH2:40][CH2:41][CH2:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46][NH:47][C:20]1[C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=3)[NH:23][C:22]=2[N:34]=[C:18]([CH2:17][C:16]2[CH:36]=[CH:37][CH:38]=[C:14]([CH:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]([F:13])([F:12])[F:11])[CH:15]=2)[N:19]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(OCc4ccccc4)C(F)(F)F)c3)nc(Cl)c12
Reactant: CN(CCCN)CCCN
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(OCc4ccccc4)C(F)(F)F)c3)nc(NCCCN(C)CCCN)c12
Temperature: 140 °C
Yield: 63.9 %

Procedure:
A mixture of methyl 2-(3-(1-(benzyloxy)-2,2,2-trifluoroethyl)benzyl)-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (0.375 g, 0.695 mmol) and N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (0.784 mL, 4.86 mmol) in MeOH (9.83 mL, 243 mmol) was heated in a microwave oven to 140° C. for 30 minutes. Then, after concentration to dryness under reduced pressure the resulting brown oil was purified by flash chromatography to afford methyl 4-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-(3-(1-(benzyloxy)-2,2,2-trifluoroethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (288 mg, 63.9% yield) as a yellow foam: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (dt, J=14.0, 6.9 Hz, 2H) 1.75 (quin, J=6.7 Hz, 2H) 2.14 (s, 3H) 2.24-2.42 (m, 4H) 2.52-2.60 (m, 2H) 3.61 (q, J=6.3 Hz, 2H) 3.88 (s, 3H) 4.10 (s, 2H) 4.49 (s, 2H) 5.17 (q, J=7.0 Hz, 1H) 7.18-7.30 (m, 5H) 7.31-7.36 (m, 1H) 7.39 (t, J=7.6 Hz, 1H) 7.44-7.53 (m, 2H) 7.58 (t, J=5.3 Hz, 1H) 7.84 (dd, J=8.2, 1.4 Hz, 1H) 8.00 (d, J=1.4 Hz, 1H) 8.28 (d, J=8.2 Hz, 1H); MS m/z 649.3 (M+H)+; HPLC 97.6% @ 220 nm and 95.5% @ 254 nm, RT=1.96 minutes.