Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]2)=[CH:2]1.N1C=CC=CC=1.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1C=CC=CC=1>[CH:28]1([C:34]([NH:21][C:19]([NH:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:17][CH2:16]2)=[O:20])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(NC(=O)C1CCCCC1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
To a suspension of 1-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea (0.35 g) in dry benzene (2 ml) was added anhydrous pyridine (0.12 g) and then cyclohexanoyl chloride (0.18 g). After refluxing the mixture for 2 for hours, the title compound was filtered off, washed, dried and converted in ethanolic hydrogen chloride to the hydrochloride (0.52 g) m.p. 236.3° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)=[O:27])=[CH:21][CH:20]=3)[C:15]([CH:17]=O)=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1.O>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:7][C:8]1[C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)=[O:27])=[CH:21][CH:20]=3)[C:15]([CH:17]=[CH2:1])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0 g, 9.06 mmol) was suspended in 1,4-dioxane (20 mL) and treated with methyltriphenylphosphonium bromide (3.2 g, 9.06 mmol). The mixture was allowed to stir at rt for 30 min. A yellow suspension formed then Intermediate AF (1-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea) (2.0 g, 4.53 mmol) in 1,4-dioxane (10 mL) was slowly added and the reaction was stirred at rt for 4 hr. The reaction was slowly poured into vigorously stirring water. The mixture was allowed to stir for 1 hr. The solid was filtered and rinsed with water and MeOH. A light brown solid was isolated (1.2 g, 60%). 1H-NMR (DMSO-d6) δ 9.90 (s, 1H), 9.77 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.06-8.05 (m, 2H), 7.84 (s, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.36 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 6.39 (dd, J1=11.3, J2=17.6 Hz, 1H), 5.63 (dd, J1=1.7, J2=17.5 Hz, 1H), 5.12 (dd, J1=1.5, J2=11.1 Hz, 2H). MS [M+H]+=440.0; LCMS RT=2.88.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:24])[N:17]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:23]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of cis-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.005 mmol) in absolute ethanol (25 mL) was treated with palladium 10 wt. % on activated carbon (0.100 g, 0.201 mmol) and ammonium formate (0.317 g, 5.03 mmol). The reaction mixture was stirred at 80° C. for 2 h; no starting material was seen by thin layer chromatography. The reaction mixture was filtered through a pad of celite, which was washed with ethanol (500 mL). The organic layer was removed under reduced pressure. The resulting solid was dried over night under high vacuum to give 0.406 g (99%) of cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol. 1H NMR (DMSO-d6, 400 MHz) δ 8.204-8.194 (m, 2H), 7.472-7.437 (m, 2H), 6.947-6.912 (m, 2H), 4.791-4.744 (m, 1H), 2.418 (m, 9H), 2.249-2.243 (m, 2H), 2.193 (s, 3H), 2.077-2.050 (m, 2H), 1.688-1.666 (m, 2H), 1.656-1.578 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 3.47 min (99%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][CH:5]=1>O1CCOCC1.C(Cl)(Cl)Cl>[Br:1][C:21]1[C:20]2[C:15]([C:14]3[NH:13][S:12](=[O:25])(=[O:24])[N:11]([CH3:26])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)[C:23]=3[CH:22]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: BrBr
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CN1C(c2ccc(F)cc2)c2cc(Br)c3cccnc3c2NS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
Bromine (7.48 μl, 0.15 mmol) was added to a solution of 1-(4-fluoro-phenyl)-2-methyl-1,4-dihydro-2H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 382 (50 mg, 0.15 mmol) in dioxane:chloroform (1:1, 4 ml) at 0° C. and the mixture was stirred at 0° C. for 1 h. The resulting precipitate was collected by filtration and dried. The resulting solid was triturated from MeOH to give the title compound (17 mg, 28%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a suspension of 0.102 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in 10.0 ml of ethanol is added 0,015 g of sodium borohydride. The reaction mixture is stirred for 1.5 hours at room temperature and then diluted with 50 ml of water. The aqueous layer is extracted with 5:1 chloroform-methanol and the combined organics dried over magnesium sulfate, filtered and concentrated in vacuo to yield 0.103 g of the desired product. CI MASS SPEC 247(MH+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22]>CN(C=O)C.ClCCl>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Reactant: C[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCSC
Temperature: 80 °C
Yield: 100.2 %

Procedure:
Sodium thiomethoxide (0.3 g, 3.79 mmol) was added to a solution of 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.0 g, 3.16 mmol) in 15 mL of DMF and heated for 3 hours at 80° C. The reaction mixture was allowed to cool to ambient temperature, diluted with dichloromethane, and washed with water. The aqueous layer was extracted with several additional portions of dichloromethane and the combined organic layers were washed with water, washed with brine, dried over magnesium sulfate, and concentrated to afford 1.04 g of 1-(4-methylthiobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:10]([CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:24])[N:10]2[CH3:23])=[CH:19][CH:18]=1
Reactant: CN1C(=O)N(Cc2ccccc2)CC1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)N(Cc2ccccc2)CC1Cc1ccc(N)cc1
Reaction time: 24 h

Procedure:
A mixture of the product from step (a) (2.2 g), 10% Pd/C (400 mg) and 2N aqu. HCl (4.3 ml) in ethanol/water (27.8 ml, 3:5 v/v) was hydrogenated at room temperature and atmospheric pressure for 24 hours (uptake ca 200 ml). The mixture was filtered through celite, the residue washed with hot water and the filtrate evaporated in vacuo to give the desired product as a white solid (2.1 g).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH:26]([CH3:28])[CH3:27])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>>[CH:26]([O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[C:7]=2[N:8]=1)([CH3:28])[CH3:27]
Reactant: CC(C)Oc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)Oc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 95 using 8-chloro-N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 115) and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Yield: 88.7 %

Procedure:
Prepared by general procedure III from 2-amino-2-methyl-1-propanol (8.91 g, 100 mmol) and commercially available 3-bromobenzenesulfonyl chloride (2.88 mL, 20 mmol) to give the title compound as a white solid (5.47 g, 89%). MS (ISN) 306.1 [(M−H)−], 308.2 [(M+2−H)−]. mp 138° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][Cl:23])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CO)ccc3o2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1

Procedure:
A mixture of 4-tert-butyl-2-(5-hydroxymethylbenzofuran-2-yl)thiazole (2.82 g) and thionyl chloride (1.4 ml) in dichloromethane (30 ml) was stirred under reflux for 1 hour. After being cooled, the resulting mixture was adjusted to pH 7 with aqueous sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, concentrated under reduced pressure to give crystals of 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole (2.93 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(-c2ccc(OCc3ccccc3)cc2)c1

Procedure:
9.0 g (32 mmol) of sodium metaborate octahydrate and 1.3 g (1.82 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 200 ml of water and 40 ml of THF, a solution of 55 g (171 mmol) of 1,3,5-tribromobenzene in 80 ml of THF is added, and a solution of 10 g (45.5 mmol) of 4-benzyloxybenzeneboronic acid is added dropwise under reflux. The batch is heated under reflux for 16 h, added to water and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on silica gel with heptane/ethyl acetate (19:1) and recrystallised from ethanol, giving 4′-benzyloxy-3,5-dibromobiphenyl as colourless crystals.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[O:37]=[C:38]([N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[O:37]=[C:38]([N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(CC(=O)N5CCCC5)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 197.3 mg of 1-(2-oxo-2-pyrrolidin-1-ylethyl)piperazine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH2:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH:15][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17]([CH3:16])(=[O:18])=[O:19])[CH:22]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)s2)CCO1
Reactant: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Product: CS(=O)(=O)Nc1cccc(CC(=O)NC[C@H]2CN(Cc3ccc(Cl)s3)CCO2)c1
Yield: 55 %

Procedure:
Example 49 was prepared in an analogous manner to Example 44 using a mixture of Intermediate 14 (0.1 g) and Intermediate 18 (0.1 g) to give the title compound (0.102 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(C2CCCN2)ccn1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccncc2)cc1

Procedure:
The title compound, pale brown solid, m.p. 158° C. and MS: m/e=302 (M+) was prepared in accordance with the general method of example 1e from (RS)-4-(2-pyrrolidinyl)-pyridine and toluene-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[N:42]=[C:43]=[O:44]>CN(C=O)C>[Cl:18][C:13]1[C:12]([OH:19])=[C:11]([S:8]([N:7]([CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[C:3]([CH2:2][NH:1][C:43]([NH:42][C:36]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=3[F:34])=[O:44])[CH:4]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)(=[O:9])=[O:10])[CH:16]=[C:15]([Cl:17])[CH:14]=1
Reactant: NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(CN(Cc2ccc(C(F)(F)F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of N-(3-(aminomethyl)benzyl)-3,5-dichloro-2-hydroxy-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide (40 mg, 0.08 mmol) in DMF (2 mL) was added 2,4-difluorophenyl isocyanate (10.0 μL, 0.09 mmol). The resulting mixture was stirred at rt for 3 h under nitrogen. The mixture was concentrated and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated and lyophilized to give a white solid (30 mg, 57%). 1H NMR (CD3OD): δ 7.59 (d, J=2.8 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.39-7.37 (m, 4H), 7.31 (t, 7.7 Hz, 2H), 7.24 (d, J=7.7 Hz, 2H), 7.19 (t, J=7.1 Hz, 2H), 7.09 (m, 2H), 7.02 (s, 1H), 6.89 (d, J=6.6 Hz, 1H), 4.48 (s, 2H), 4.40 (s, 2H), 4.23 (s, 2H); MS (ESI): (M+H)+=714.2.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:35][C@@H:36]1[C@H:41]([CH3:42])[CH2:40][CH2:39][CH2:38][N:37]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].[C:53]1(=[O:63])[NH:57][C:56](=[O:58])[C:55]2=[CH:59][CH:60]=[CH:61][CH:62]=[C:54]12>C1COCC1>[O:58]=[C:56]1[C:55]2[C:54](=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:53](=[O:63])[N:57]1[CH2:35][C@@H:36]1[C@H:41]([CH3:42])[CH2:40][CH2:39][CH2:38][N:37]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110 %

Procedure:
A solution of PPh3 (21.5 g, 82 mmol) in 30 ml of THF was cooled to 0° C. DIAD (16.1 mL, 82 mmol) was then added dropwise and reaction stirred for 20 min. A solution of (2S,3R)-benzyl 2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (8.7 g, 32.9 mmol) in 15 mL THF was then added dropwise and stirred at 0° C. for 30 min. Phthalimide (6.3 g, 42.7 mmol) was then added and the reaction was warmed to rt overnight. The resulting suspension was concentrated in vacuo, diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound (14.2 g, 110%, DIAD contamination), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.72-7.71 (m, 1H), 7.62-7.60 (m, 3H), 7.17-7.13 (m, 3H), 7.05-7.04 (m, 1H), 6.98-6.96 (m, 1H), 4.76-4.69 (m, 1H), 4.54-4.39 (m, 1H), 4.03-3.98 (m, 2H), 3.63-3.54 (m, 1H), 3.25-3.07 (m, 1H), 1.91-1.80 (m, 1H), 1.73-1.54 (m, 2H), 1.47-1.25 (m, 2H), 1.07-1.04 (m, 3H). ESI-MS (m/z): 263.93 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)OC)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 50 %

Procedure:
To a solution of methyl 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (3.42 g) in a mixture of tetrahydrofuran (20 mL) and ethanol (15 mL) was added 1M aqueous sodium hydroxide solution (18 mL), and the mixture was stirred at 50° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was washed with diethyl ether. To the aqueous layer was added 1M hydrochloric acid (18.5 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual amorphous solid was solidified with diethyl ether to give the title compound (1.66 g) as a pale yellow solid. MS 553 (MH+).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]2[CH2:12][C@H:11]2[C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]=2)[CH:4]=1)[NH2:2].CN(C)[C:25](=[N:27][C:28](=O)[CH2:29][O:30][CH3:31])[CH3:26]>C(O)(=O)C>[CH3:31][O:30][CH2:29][C:28]1[N:1]([C:3]2[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C@@H:10]3[CH2:12][C@H:11]3[C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH:4]=2)[N:2]=[C:25]([CH3:26])[N:27]=1
Reactant: COCC(=O)N=C(C)N(C)C
Reactant: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Solvent: CC(=O)O
Product: COCc1nc(C)nn1-c1cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)nc(C)n1
Temperature: 25 °C

Procedure:
A solution of 2-((1R,2R)-2-(6-hydrazinyl-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-7, 25.0 mg, 0.0850 mmol, 1.0 eq) in acetic acid (3 mL) was added to a round bottom flask containing N-(1-(dimethylamino)ethylidene)-2-methoxyacetamide (200 mg, 1.26 mmol, 14.9 eq; prepared according to procedure 2-1). The acetic acid solution was heated at 100° C. for 30 minutes, allowed to cool to room temperature and concentrated to dryness. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by reverse phase liquid chromatography (H2OCH3CN gradient w/ 0.1% NH4OH present) to afford 2-((1R,2R)-2-(6-(5-(methoxymethyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (4-8) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.69 (m, 2H), 7.24 (m, 3H), 5.11 (s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 2.83 (m, 2H), 2.69 (s, 3H), 2.56 (s, 3H), 2.04 (m, 1H), 1.98 (m, 1H). HRMS m/z (M+H) 390.2039 found, 390.2037 required.
Reaction SMILES: C1(C)C(C)=CC=CC=1.Cl.[NH2:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=1[SH:20].[CH2:21]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#N)[CH3:22]>C(O)C>[CH2:21]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[S:20][C:12]2[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=2[N:10]=1)[CH3:22]
Reactant: CCOC(=O)CCCCCC#N
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCCCc1nc2c(F)c(F)cc(F)c2s1
Yield: 39.7 %

Procedure:
To xylene (6 ml) was added 2-amino-3,4,6-trifluorothiophenol hydrochloride (647 mg, 3 mmol), 6-cyanohexanoic acid ethyl ester (507 mg, 3 mmol) and ethanol (0.5 ml) and the mixture was heated to reflux for 60 hours under a nitrogen stream. The resultant reaction mixture was washed with water, dried and then evaporated to yield a residue, which was purified on a silica gel column to give 6-(4,5,7-trifluorobenzothiazol-2-yl)hexanoic acid ethyl ester (395 mg, 40%) as an oil.