Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4[N:30]=[C:29]([CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)[O:28][N:27]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C(O)=O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4[N:30]=[C:29]([CH:31]5[CH2:36][CH2:35][N:34]([CH3:1])[CH2:33][CH2:32]5)[O:28][N:27]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C=O
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCNCC2)n1
Solvent: O=CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCN(C)CC2)n1
Temperature: 95 °C
Yield: 69.3 %

Procedure:
Aqueous formaldehyde (37%, 894 ml, 12.0 mmol) was added to a solution of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine (1 g, 2.0 mmol) in formic acid (2 ml). The mixture was heated at 95° C. for two hours. The volatiles were removed under vacuum, the residue was dissolved in CH3OH and the pH of the solution was adjusted to 9 by addition of Biorad AG® 1-X8 hydroxide form resin. The solution was filtered, concentrated in vacuo and the residue was crystallized from MeOH/H2O to give N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine (714 mg; 69% yield). 1H NMR (400 MHz; DMSO-d6): 1.69-1.82 (m, 2H), 1.97-2.05 (m, 4H), 2.16 (s, 3H), 2.71-2.78 (m, 2H), 2.98-3.10 (m, 1H), 3.96 (s, 3H), 5.44 (s, 2H), 7.39 (s, 1H), 7.62 (d, 1H), 7.83 (s, 1H), 7.87 (dd, 1H), 8.22 (d, 1H), 8.53 (s, 1H), 9.63 (s, 1H); MS (EI) for C24H24Cl2N6O3: 515.07 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33](O)[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:32]=1
Reactant: COC(=O)c1cc(O)nc(OC)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(OC)nc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 2-hydroxy-6-methoxy-isonicotinic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Light yellow oil (77%). MS (Turbo Spray): m/z=556.2 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH:10](OCC)[O:11]CC)[N:5]=[C:4]([O:17][C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:3]=1.ClC(Cl)(Cl)C(O)=O>ClC(Cl)Cl.O.CCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH:10]=[O:11])[N:5]=[C:4]([O:17][C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[CH:3]=1
Reactant: CCOC(C#Cc1cc(C)cc(Oc2cc(C(F)(F)F)nn2C)n1)OCC
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C#CC=O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 39.7 %

Procedure:
A suspension of 4-methyl-6-(3,3-diethoxyprop-1-ynyl) -2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (2.2 g, 5.7 mmol) in trichloromethane (100 ml), water (5 ml) and trichloroacetic acid (3 g) is heated overnight at reflux. After cooling, the reaction mixture is diluted with pentane:ethyl acetate 1:1 and the organic phase is washed with water and a saturated aqueous solution of sodium bicarbonate and dried. 40% of the product (0.7 g) is obtained by flash chromatography as nearly less crystals of mp 73° C.
Reaction SMILES: [C:1]1(=O)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:10]([N:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCCCCO1
Reactant: CCCCCCCCN
Product: CCCCCCCCN1CCCCCC1=O
Yield: 25.5 %

Procedure:
Following example 5, heating 17.5 g (0.153 M) of 6-hexanolactone and 22 g (0.17 M) of 1-aminooctane at 180° for 29 hr. gave 8.8 g (27%) of product; b.p. 155°-160°/0.5 mm.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[S:17][CH:16]=1)(C)(C)C>>[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[C:18]1[S:17][CH:16]=[C:15]([NH2:14])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2ncccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1csc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4 N hydrochloric acid-dioxane solution (8 mL) was added to tert-butyl(5-(pyrimidin-2-yl)thiophen-3-yl)carbamate obtained in the above-described Step (544 mg), and the reaction solution was stirred at room temperature for 90 minutes. The solvent was evaporated under vacuum to obtain 5-(pyrimidin-2-yl)thiophen-3-amine hydrochloride as a brown solid.
Reaction SMILES: [NH:1]([C:29]([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:46][C:47]1[C:52](O)=[C:51]([F:54])[C:50]([F:55])=[C:49]([F:56])[C:48]=1[F:57].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[NH:1]([C:29]([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C@H:2]([C:26]([O:28][C:52]1[C:47]([F:46])=[C:48]([F:57])[C:49]([F:56])=[C:50]([F:55])[C:51]=1[F:54])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g (2.51 mmol) of Fmoc-Asn(Trt)-OH are dissolved in 15 ml of tetrahydrofuran. 0.51 g (2.76 mmol) of pentafluoro-phenol is added, the solution is cooled to 0° and then 0.57 g (2.76 mmol) of dicyclohexyl-carbodiimide is also added in solid form. It is stirred at 0° for 30 minutes, at room temperature for 2 hours and again at 0° for 30 minutes. The dicyclohexylurea which has crystallized out is filtered off, and the filtrate is evaporated to dryness and triturated with 40 ml of diisopropyl ether. The powdery residue is filtered off, dried and recrystallized from methylene chloride/petroleum ether. Fmoc-Asn(Trt)-OPfp is obtained; m.p. 154°-156°, [α]D20 =-7.8° (THF).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:44])[C@@H:27]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH3:30])=[CH:22][CH:21]=1>C1COCC1>[F:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:26]([OH:44])([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[C@@H:27]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CCC[C@@H](C(=O)c1ccc(OC)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)C(O)(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-fluoronaphthalene (229 mg, 1.02 mmol) in THF (6 mL) at −78° C. was added BuLi (2.5 M in hexanes, 0.434 mL, 1.086 mmol), then the solution was stirred for one hour. A solution of t-butyl (R)-4-[2-(4-methoxyphenyl)-1-propylethan-2-one-1-yl]benzoate (prepared using the procedure for INTERMEDIATE 4, 250 mg, 0.678 mmol) in THF (2 mL) was added and the solution was stirred for an additional hour. The solution was quenched with saturated NH4Cl (aq), then diluted with EtOAc (50 mL). The organic layer was separated, washed with water then brine, dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound. LC1 1.30 min. [M+H−H2O]+ 497.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:4]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccccc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ccccc1C#N
Yield: 97 %

Procedure:
Alternatively, 2-ethynylbenzonitrile (a3) may be prepared according to the procedures set forth in M. J. Wu et al. (1999), Organic Letters, 1 (5):767-768, which is incorporated herein by reference in its entirety. Specifically, palladium-catalyzed coupling reaction of trimethylsilylacetylene with 1,2-diiodobenzene produced 2-(2-trimethylsilylethynyl)iodobenzene in 58% yield; 2-(2-trimethylsilylethynyl)iodobenzene was then coupled with Zn(CN)2 using palladium(0) as a catalyst to give 2-(2-trimethylsilylethynyl)benzonitrile in 45% yield; and finally, 2-(2-trimethylsilylethynyl)benzonitrile was treated with tetrabutylammonium fluoride to give 2-ethynylbenzonitrile (a3) in 97% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A 500 ml flask was charged with 3-bromophenol (A) (25 g, 144 mmol), THF (200 ml) and triethylamine (14.67 g, 145 mmol). The flask was cooled to 0° C. in an ice bath, and chlorotriethylsilane (21.8 g, 144 mmol) was added dropwise. The mixture was allowed to stir at room temperature to completion over 2 h. The hydrochloride salt was then filtered. Removal of solvents followed by flash chromatography afforded 3-bromo-O-triethylsilylphenol (J) as a clear liquid (30.4 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:8]2=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)=O.O.[NH2:27][NH2:28]>C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]2[C:8]3=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=[C:7]3[CH:6]=[C:5]2[C:3]2[O:2][CH:1]=[N:27][N:28]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Yield: 71.4 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester obtained in Example 33 (5) (0.3 g) in ethanol (9 ml), hydrazine monohydrate (0.22 g) was added at 15 to 30° C. and the mixture was heated under reflux for 6 hours, followed by further addition of hydrazine monohydrate (0.11 g), and the mixture was heated under reflux for 4 hours. Furthermore, hydrazine monohydrate (0.11 g) was added to the mixture, followed by heating under reflux for 16 hours. The reaction solution was concentrated under reduced pressure. To the resulting crude product was added orthoformic acid triethyl ester (25 ml) and the mixture was heated under reflux for 18 hours. The reaction solution was separated using silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 220 mg of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([C:17]1[CH2:18][O:19][CH2:20][CH:21]=1)(=O)=O>>[CH2:1]([C:8]1[C:17]2[CH2:18][O:19][CH2:20][C:21]=2[C:10]([OH:9])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ncco2)cc1
Reactant: CS(=O)(=O)C1=CCOC1
Product: Oc1cnc(Cc2ccccc2)c2c1COC2

Procedure:
11.2 g (70 millimoles) of 2-benzyloxazole and 10.5 g (70 millimoles) of 3-methylsulfonyl-2,5-dihydrofuran are heated for 7 hours at 160°. The unconverted starting compounds are distilled off in a high vacuum and the distillation residue is extracted with methylene chloride. The 4-benzyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol contained in the extract is separated off by chromatography over silica gel (using methylene chloride and ethyl acetate). 4.3 g are obtained. Recrystallization from benzene/methylene chloride gives a pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].S(Cl)(Cl)=O.[CH2:30](O)[CH3:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([O:20][CH2:30][CH3:31])=[O:19]
Reactant: COc1cc2nccc(Sc3ccc(F)cc3C(=O)O)c2cc1OC
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)ccc1Sc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Yield: 83 %

Procedure:
2-(6,7-Dimethoxy-quinolin-4-ylsulfanyl)-5-fluoro-benzoic acid (76 mg) was suspended in ethanol (387 mg), and the suspension was cooled at 0° C. Thionyl chloride (50 mg) was gradually added dropwise thereto, and the mixture was then heated under reflux for 20 min. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was neutralized with a 20% aqueous sodium hydroxide solution and was then extracted with ethyl acetate. Next, the ethyl acetate layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (68 mg, 84%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:7].C(O)C.[OH-].[Na+].[Na]>O.CC(C)=O>[CH3:2][NH:3][CH2:4][CH2:5][CH:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[OH:7]
Reactant: CNCCC(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: CNCCC(O)c1cccs1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a mixture of 3-(methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (10.3 g, 50 mmol) and ethanol (35 mL) at 4° C. sodium hydroxide (4.0 g of a 50% aqueous solution) was added in about 5 minutes. Afterwards, neat sodium borhydride (0.95 g, 25 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 h at the same temperature, then acetone (10.0 mL) was added dropwise in 5 minutes and the mixture was stirred for 10 additional minutes. Water (20 mL) was then added. Afterwards, the mixture was concentrated about 5 times under vacuum and the residue was extracted with tert-butyl methyl ether (2×20 mL). The collected organic phases were finally concentrated under vacuum affording an orange oil which crystallised spontaneously after a few hours. Finally, an orange solid was obtained (7.2 g, 84% yield). This compound can then be used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH2:5][C@@H:6]1[CH2:11][C@H:10]([O:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:9][CH2:8][N:7]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].[OH-].[Na+].Cl>CO>[C:39]([O:38][C:36]([N:7]1[CH2:8][CH2:9][C@@H:10]([O:12][C:13]2[C:14]3[C:21]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:11][C@H:6]1[CH2:5][CH2:4][C:3]([OH:43])=[O:2])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)CC[C@@H]1C[C@H](Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCN(C(=O)OC(C)(C)C)[C@H](CCC(=O)O)C4)c23)cc1
Temperature: 0 °C

Procedure:
Dissolve 35 mg (0.06 mmol) of 3-[(2R,4R)-1-(tert-butoxycarbonyl)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-2-yl]propanoic acid methyl ester in 0.1 ml of methanol, cool to 0° C. and add approx. 240 mg of 10% sodium hydroxide solution. Stir the mixture at approx. 40° C. for several hours, then at RT overnight. Then slightly acidify the reaction mixture with 1N hydrochloric acid (pH approx. 3) and extract repeatedly with dichloromethane. Wash the combined organic phases with satd. sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. The target compound is obtained in quantitative yield (34 mg) and is not purified further.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:22]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=6)[CH:27]=5)=[CH:21][N:20]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][N:26]1[CH:27]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:7][CH2:6][CH2:5][N:4]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:3][CH2:2]5)=[CH:9][CH:10]=4)[CH:15]=3)[N:20]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=3)(=[O:38])=[O:37])[CH:21]=2)[CH:24]=[N:25]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCNCC5)cc4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(4-(1,4-diazepan-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.161 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.241 mmol), DIPEA (62 mg, 0.48 mmol) and ethanol (3 mL) to get 100 mg (91.7% yield) of the titled compound. MS: m/z=679.6 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:38][C:39]([Cl:44])([Cl:43])[C:40](Cl)=[O:41].C(OCC)(=O)C.CCCCCC>ClCCl>[Cl:38][C:39]([Cl:44])([Cl:43])[C:40]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:41]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2′dimethyl-biphenyl-4-yl)-methanone of Step C (8.38 mmol) and triethylamine (16.76 mmol) in dichloromethane (30 mL) at ˜5° C. was added, rapidly dropwise, trichloroacetyl chloride (25 mmol). The mixture was allowed to stir and warm to room temperature overnight. The mixture was washed with 0.1N hydrochloric acid and dilute brine, then dried over anhydrous sodium sulfate and evaporated to leave a light green oil. The title compound was obtained pure as a light yellow crystalline solid by treatment with hot ethyl acetate/hexane (3/1), mp 212-214° C.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]([C:6]1[C:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[N:8][S:9][C:10]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17](OC)=[O:18])=[O:13])=[O:5].CO>O1CCCC1>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]([NH:11][C:10]1[S:9][N:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:6]=1[C:4]([NH2:3])=[O:5])=[O:13]
Reactant: COC(=O)CCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCO
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Sodium borohydride (24.0 g 0.636 mol) was added to a solution of methyl 3-[({[4-(aminocarbonyl)-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]propanoate (25.0 g, 0.0636 mol) in tetrahydrofuran (1200 mL). The resulting suspension was heated to reflux. Methanol (200 mL) was added drop wise over 1 hr. and the reaction was refluxed for 1 hr. The reaction mixture was cooled to ambient temperature and solvent concentrated in vacuo. The residue taken in EtOAc (600 mL) and washed with water, 2 N HCl and brine then dried (sodium sulfate), filtered, solvent concentrated in vacuo to give the title compound as a yellow solid (18.8 g, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCN
Product: CCNc1ccncc1[N+](=O)[O-]

Procedure:
In a manner similar to example 31, the title compound was prepared from 4-chloro-3-nitropyridine, prepared according to published procedure [J. Med. Chem. 1996, 39, 487–493], and ethylamine. 1H-NMR (CDCl3): δ 9.22 (1H, s), 8.30 (1H, d), 8.10 (1H, br s), 6.71 (1H, d), 3.40 (2H, m), 1.39 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH2:16].[Na].FC(F)(F)C([O-])=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:16][CH2:15][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccccn1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CN1CCc2c(c3ccccc3n2CCc2ccccn2)C1
Yield: 20.6 %

Procedure:
The title compound was prepared according to General Method 3. 2,3,4,5-Tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 3) (200 mg, 1 mmol), 2-vinylpyridine (0.26 mg, 2.5 mmol), sodium (5 mg, 0.21 g atom) and CuSO4 (5 mg, catalytic) in ethanol (4 mL) at 120° C. for 16 h (overnight) to obtain 60 mg of 2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).