Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C:7]2=[CH:8][CH:9]=1.[C:35]1(=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[NH:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:45]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C:7]2=[CH:8][CH:9]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCO)ccc43)c21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCN5C(=O)c6ccccc6C5=O)ccc43)c21
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To a solution of (R)-tert-butyl 5-(2-hydroxyethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.021 g, 0.045 mmol) in THF (0.2 mL) was added isoindoline-1,3-dione (0.020 g, 0.14 mmol) and PS—PPh3 (0.081 g, 0.14 mmol). The solution was cooled to 0° C. and DEAD (0.021 ml, 0.14 mmol) was added dropwise. The reaction was allowed to stir with warming to about room temperature for 2 hours. The reaction was filtered and the solvent was evaporated. The crude residue was purified by column chromatography (1-3% MeOH/DCM) to yield (R)-tert-butyl 5-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.014 g, 52%). LCMS (APCI+) m/z 594 [M+H]+; Rt=4.15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[C:4]([CH2:18][NH:19][C:20](=[O:41])[CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][C:31]([F:39])([F:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:23]=2[F:40])[CH:3]=1.Cl>CCOC(C)=O>[NH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:18][NH:19][C:20](=[O:41])[CH2:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][C:31]([F:38])([F:39])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:23]=1[F:40]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CNC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCc1ccc(Cl)cc1CNC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1F

Procedure:
To a 0° C. solution of 0.04 g (0.065 mmol) tert-butyl 2-[4-chloro-2-({[(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetyl]amino}methyl)phenyl]ethylcarbamate 1-10 in 2 mL EtOAc/1 mL MeOH was passed through a steady stream of HCl gas for 5 minutes, then the reaction mixture was concentrated to give N-[2-(2-aminoethyl)-5-chlorobenzyl]-2-(5-chloro-2-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetamide 1-11. 1H NMR (400 mHz, CD3OD) δ8.71 (d, 1H, J=4.58 Hz); 8.15 (apparent t, 1H, J=7.51 Hz); 7.89 (d, J=8.06 Hz); 7.70 (m, 2H); 7.29(d, 1H, J=1.84 Hz); 7.28 (dd, 1H, J=2.01 and 8.24 Hz); 7.23 (d, 1H, J=8,24 Hz); 4.42 (s, 2H); 4.36 (t, 2H, J=13.5 Hz); 3.80 (s, 2H); 3.41 (m, 2H); 3.02 (m, 2H). Mass Spectrum (electrospray) M+H=512.2
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[F:37])[NH2:33]>O1CCOCC1.C(#N)C>[ClH:2].[Cl:29][C:30]1[CH:31]=[C:32]([NH:33][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Temperature: 70 °C
Yield: 153.4 %

Procedure:
4.0M HCl in Dioxane (1 ml) was added to a suspension of tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (331 mg, 0.84 mmol) and 3-chloro-4-fluoroaniline (134.5 mg) in acetonitrile (10 ml). The reaction mixture was stirred and heated at 70° C. for 4 hours. The resulting precipitate was filtered hot, washed with acetonitrile and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride (566 mg); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]=1[CH3:12].[CH3:15][NH2:16]>>[CH3:15][N:16]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]([CH3:12])=[C:2]([CH3:1])[C:3]1=[O:4]
Reactant: Cc1c2c(oc(=O)c1C)CCCC2=O
Reactant: CN
Product: Cc1c2c(n(C)c(=O)c1C)CCCC2=O

Procedure:
Prepared from 3,4-dimethyl-5,6,7,8-tetrahydro-cumarin- 5-one and methanolic methylamine solution over a period of 15 hours at ambient temperature.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH2:24][CH2:23]1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(C2CCN(c3ccc(CN4CCOCC4)cc3)CC2)CC1

Procedure:
Prepared from the product of Example 19 and N-methylpiperazine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:41][NH:42][O:43][CH3:44]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:42]([O:43][CH3:44])[CH3:41])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To the solution of compound 4-bromo-2-methylbenzoic acid D-1 (50 g, 0.23 mol) in DCM (500 mL) was added EDCI (48 g, 0.25 mol), HOBt (34.1 g, 0.25 mol), NMM (50.5 g, 0.50 mol) and N,O-dimethylhydroxylamine hydrochloride (24.3 g, 0.25 mol). The reaction mixture was stirred at room temperature overnight, diluted with DCM, washed with H2O (300 mL), 1 N HCl (300 mL), and saturated sodium bicarbonate solution (300 mL), dried over sodium sulfate, and concentrated to give the desired product D-2 (55 g, yield 91.6%) as yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][OH:6].[C:7]([O:16][CH3:17])(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>[Cu]I.CN(C=O)C>[OH:6][CH2:5][C:4]#[C:3][CH2:2][C:14]#[C:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([O:16][CH3:17])=[O:15]
Reactant: OCC#CCCl
Reactant: C#CCCCCCC(=O)OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCC#CCC#CCO
Temperature: 30 °C
Reaction time: 48 h
Yield: 63.3 %

Procedure:
23.00 g (0.22 mol) of 4-chloro-2-butyn-1-ol (I), 33.93 g (0.22 mol) of methyl 7-octynoate (II), 30.41 g (0.22 mol) of K2CO3, 32.98 g (0.22 mol) of NaI, and 20.95 g (0.11 mol) of CuI were added to 440 ml of DMF, followed by stirring at 30° C. for 48 hours. The reaction mixture was quenched by adding to a saturated aqueous NH4Cl solution (200 ml) (hereinafter, referred to as “sat. NH4Cl aq.”), then the resulting mixture was extracted with ethyl acetate. The extract was washed with water, concentrated, and the concentrate was purified over a silica gel column (hexane/ethyl acetate=8/2 to 4/6 (volume ratio)) to obtain 30.97 g of methyl 12-hydroxydodeca-7,10-diynoate having a GC purity of 93.3% (yield: 59.1% th). The structure thereof was confirmed by NMR.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([CH3:13])([N+:10]([O-])=O)[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1(C)C=CC=CC=1.[Ni]>[NH2:10][C:7]([CH3:13])([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][OH:9]
Reactant: CC(C)(C)OCC(C)(CO)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC(N)(CO)COC(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of 150 g (0.78 mol) of 3-tert-butoxy-2-methyl-2-nitro-propan-1-ol [prepared according to Example 1c or 1c′] in 700 ml of toluene in a pressure vessel is added 15 g of Raney-Ni and 40 ml of a pH 7.00 buffer [NORMEX (RTM), Carlo Erba]. Through the closed autoclave is added at room temperature hydrogen under 50-60 bar pressure. The reaction mixture is heated to 40° C. and maintained at this temperature for 8 hours. The reaction mixture is then cooled to room temperature, diluted with toluene, filtered and the filtrate concentrated using a vacuum rotary evaporator. The residue yields 2-amino-3-tert-butoxy-2-methyl-propan-1-ol (compound 301, Table 1), pale green solid, m.p. 30-35° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.COC1C=CC(C[N:36]2[C:41](=[O:42])[N:40]([CH3:43])[C:39]3[CH:44]=[CH:45][C:46](B4OC(C)(C)C(C)(C)O4)=[CH:47][C:38]=3[S:37]2(=[O:58])=[O:57])=CC=1.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[CH3:43][N:40]1[C:39]2[CH:44]=[CH:45][C:46]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:47][C:38]=2[S:37](=[O:58])(=[O:57])[NH:36][C:41]1=[O:42]
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: COc1ccc(CN2C(=O)N(C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3S2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)NS(=O)(=O)c2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)ccc21
Temperature: 25 °C

Procedure:
Compound 2b was subjected to Suzuki coupling conditions using the methods described in Example 1, Step G, with compound 40b and the resulting product was deprotected with TFA at 70° C. for 30 min. The reaction mixture was allowed to cool to rt and concentrated. The residue obtained was dried under reduced pressure overnight, suspended in ETOAc (10 mL) and sonicated for 10 min. The solid formed was collected by suction filtration and dried under reduced pressure to obtain the title compound 24. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.67-8.78 (m, 1H), 8.04-8.23 (m, 7H), 7.88-7.98 (m, 1H), 7.65-7.78 (m, 3H), 7.51 (s, 1H), 4.33 (br. s., 4H), 3.78-3.91 (m, 4H), 3.51 (s, 3H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])[CH2:3][OH:4].N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:31](C(O)=O)[C@@H](C)OC(C)(C)C>>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6])[C@@H:3]([CH3:31])[OH:4]
Reactant: O=C(N[C@@H](CO)C(=O)OCC(Cl)(Cl)Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: C[C@@H](O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Yield: 68 %

Procedure:
According to the procedure used for the synthesis of Fmoc-Ser-OTce, Fmoc-Thr(OtBu)-OH (1 g, 2.5 mmol) provided Fmoc-Thr-OTce (0.81 g, 1.7 mmol, 68% overall yield for two steps).
Reaction SMILES: C([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[CH:17][CH:16]=2)[N:10]=1)CCCCCCC.[CH2:24](Cl)[CH2:25]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:22]([C:14]1[CH:13]=[N:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:21])=[CH:22][CH:23]=2)=[N:10][CH:9]=1)[CH2:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:24][CH3:25]
Reactant: CCCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.84 G. of 4-(4-n-octylpyrimid-2-yl)-benzoic acid amide are maintained at reflux for 80 minutes in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride with stirring. The mixture, diluted with ether, is washed with 2-N sodium hydroxide and then with water until neutral. The organic phase is dried over sodium sulfate and evaporated to give 1.91 g. of 5-n-octyl-2-(4-cyanophenyl)-pyrimidine which are distilled in a high vacuum; melting point 66.1°-66.5° C; clearing point 47.5° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:14]C(OC(C)(C)C)=O)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:55]([C:62]1[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.Cl>O1CCOCC1.CN(C=O)C>[NH2:14][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([NH:66][C:65]1[CH:64]=[CH:63][C:62]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:68][CH:67]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
A flask was charged with 3-benzyloxy-2-tert-butoxycarbonylaminopropionic acid (5.0 g, 16.9 mmoles), HATU (7.0 g, 18.6 mmoles) and DMF (5 mL). DIEA (8.8 mL, 50.7 mmoles) was added and the mixture was stirred for 15 minutes. 4-Phenoxyaniline (3.4 g, 18.6 mmoles) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined extract was washed sequentially with 5% lithium chloride (3×10 mL), 1N sodium bicarbonate (2×10 mL), 5% citric acid (2×10 mL), deionized water (2×10 mL) and then brine (1×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from methanol to afford a white solid. The solid was combined with 4N hydrogen chloride in dioxane (25 mL). The mixture was stirred at ambient temperature for 18 hours. Volatiles then were removed under rotary evaporation. The resultant oil was partitioned between 1N sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extract was washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude was recrystallized from methanol to give 2-amino-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (2 g, 5.47 mmoles, 33% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 9.55 (s, 1H), 7.60-7.50 (m, 2H), 7.40-7.27 (m, 5H), 7.08 (t, 1H), 7.01-6.95 (m, 3H), 4.57 (t, 2H), 3.85-3.70 (m, 3H), 1.97 (2, 2H). MS (D) for C22H22N2O3. found 363.0 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:10]=[C:11]=[S:12])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].[CH:16]([NH:18][NH2:19])=O>O1CCCC1>[CH3:14][O:13][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[C:11](=[S:12])[NH:19][N:18]=[CH:16]2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: COC(=O)c1cc(N=C=S)ccc1OC
Reactant: NNC=O
Solvent: C1CCOC1
Product: COc1ccc(-n2cn[nH]c2=S)cc1C(=O)O
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Treat a mixture of 5-isothiocyanato-2-methoxy-benzoic acid methyl ester (6.90 g, 30.91 mmol) and formic hydrazide (2.04 g, 34.0 mmol, Aldrich Chemical Company) under an argon atmosphere via syringe with anhydrous tetrahydrofuran (40 mL). After three hours, concentrate in vacuo to remove the solvent, mix the residue with 1 M NaHCO3 solution (total of 300 mL employed) in portions and transfer to a 500 mL round bottom flask. Reflux for 3 days under an argon atmosphere. Filter the hot solution, acidify with concentrated hydrochloric acid (25 mL), chill the mixture in an ice bath and collect the precipitate by vacuum filtration. Wash the filter cake with dichloromethane and dry in vacuo to afford 7.12 g of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid. Combine the filtrates and concentrate in vacuo to afford another crop of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid (1.24 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CC(C)(C)C(=O)O)c3)no2)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D100) (85 mg, 176 mmol) in THF (2 ml) at room temperature was added NaOH (2N in H2O, 440 μl, 880 mmol) and the resulting mixture was stirred at 50° C. overnight. NaOH (2N in H2O, 440 μl, 880 mmol) and THF (2 ml) were added and the resulting mixture stirred at 80° C. for two nights then cooled to room temperature. Most of THF was removed in vacuo and the resulting aqueous phase was acidified to pH 3. The precipitate formed was filtered off and washed with H2O then dried at 60° C. under vacuum to give the title compound (73 mg, 91%) as a white solid. MS (ES): C23H23ClN4O4 requires 454; found (MH+) 455.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=O)=O.[F-].[Cs+].B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.Br[C:60]1[CH:65]=[C:64]([F:66])[CH:63]=[C:62]([F:67])[C:61]=1[F:68]>C(#N)C>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:19][CH:18]=1)=[O:32])=[C:11]([C:60]1[CH:65]=[C:64]([F:66])[CH:63]=[C:62]([F:67])[C:61]=1[F:68])[CH:10]=[CH:9]2
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (10.0 g, 16.6 mmol) in degassed acetonitrile (100 mL). Add cesium fluoride (13.0 g, 83 mmol) and bis(acetato)bis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) followed by bis(neopentyl glycolato)diboron (4.5, 19.9 mmol) and plunge into a 75° C. oil bath under nitrogen. After 15 minutes, add 1-bromo-2,3,5-trifluorobenzene (7.0 g, 33.2 mmol) to the reaction and bis(acetato)bis(triphenylphosphine)palladium (500 mg) and stir at 75° C. for 2.5 hours. Cool the reaction to room temperature and filter through celite. Concentrate the filtrate in vacuo and redissolve the residue in methanol (100 mL). Add KOH (4 g) and stir at room temperature overnight. Pour the reaction into saturated aqueous ammonium chloride and extract with methylene chloride. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify on 5 SCX columns (loading with methanol and eluting with 2M NH3 in methanol) to obtain 8.4 g (100%) of the title compound. Mass spectrum (ion spray): m/z=506.4 (M+H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O.O>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:25])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
In 10 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution were added 0.81 ml (10 mmol) of pyridine and 1.4 ml (15 mmol) of phosphorus oxychloride. The resulting mixture was stirred at room temperature for 24 hours. After the completion of the reaction, thereto was added 10 ml of chloroform and the resulting mixture was poured into 20 ml of iced water to separate an organic layer. The organic layer was washed with 20 ml of water and dried over 3 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.18 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 40 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.27 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(CCOC(C)=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(CCOC(C)=O)cc1

Procedure:
4-Octanoylphenethyl acetate (17.6 g) and trifluoroacetic acid (31 mL) are charged into a 250 mL single neck round bottom flask equipped with a guard tube and stirred for a few minutes. Triethylsilane (25.7 mL) is added and the mixture is stirred overnight at room temperature. The mixture is poured onto crushed ice and then extracted with ethyl acetate (3×100 mL). The organic layer is washed with sodium bicarbonate (200 mL), then with brine solution, dried with sodium sulphate, and concentrated under vacuum to give crude as brown color liquid. The crude is purified by silica gel column using hexane as the eluent to give the title compound. Yield 10 g
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1)#[N:2].N>[Ni].CCO>[NH2:2][CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1
Reactant: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCc1c[nH]c2ccc(NC(N)=O)cc12
Yield: 44 %

Procedure:
A suspension of 11.0 g (0.05 mole) of N-(3-cyanomethyl-1H-indol-5-yl)urea in 700 ml of abs. EtOH saturated with NH3 was treated with RaNi (one spoonful, activated by washing with 1 l of abs EtOH) and hydrogenated in a Parr apparatus for 14 hours. The solution was filtered through celite and then through a millipore followed by evaporation of solvents in vacuo to give an oily solid. Trituration with EtOH afforded 8.2 g of crude white product: m.p. 187.5°-188.5°. Thin layer chromatography indicated an approximately 5% impurity (3% NH4OH - MeOH/silica gel). Dry column chromatography (1.5 g/400 g of silica gel--3% NH4OH/MeOH elluent) affords 4.8 g of pure N-[3-(2-aminoethyl)-1H-indol-5-yl]urea: m.p. 188.5°-189.5°; i.r. (KBr) 3400, 3360, 3280, 3200, and 1650 cm-1 ; nmr (d6 -DMSO) δ(TMS) 10.72 (1,S,indole NH), 8.37 (1,S,--NHCO--), 7.65 (1,d, Jmeta =2 Hz), 7.27 (1,d,Jortho =8 Hz), 7.10 (1,S,indole C2H), 7.02 (1,d of d, Jortho =8 Hz, Jmeta =2 Hz), 5.71 (2,S,--CONH2), 2.78 (4,S,--CH2CH2 --) and 2.30 ppm (2,S,--NH2).