Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][S:41]([CH3:44])(=[O:43])=[O:42])OC5C=CC=CC=5)[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:47]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:45])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[NH:47])[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)NC(=N)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phenyl 4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-(methylsulfonyl)-1-piperidinecarboximidate (Formula 22.0, prepare as described in Example 21 above) is dissolved in 2-propanol and concentrated ammonium hydroxide is added. The mixture is stirred at 25° C. for 24 h and then is evaporated to dryness. The residue is triturated with diethyl ether (2×250 ml) and the ether is discarded. The remaining product is chromatographed on a silica gel column to give the title compound (Formula 23.0).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH3:15])[C:13](=[O:16])[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH3:15])[C@H:13]([OH:16])[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC1(CC)C(=O)C(C)N(c2ccc(C#N)c(Cl)c2)C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(CC)C(=O)N(c2ccc(C#N)c(Cl)c2)[C@H](C)[C@@H]1O

Procedure:
Using 2-chloro-4-(3,3-diethyl-5-methyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (67 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.33 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as colorless crystals (yield: 34.5 mg, 51%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[N:9]#[C:10]Br>>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:10]#[N:9])=[CH:1][CH:2]=1
Reactant: N#CBr
Reactant: Oc1ccc(Br)cc1
Product: N#COc1ccc(Br)cc1
Yield: 63 %

Procedure:
Analogous to Example 1, p-bromophenol was reacted with cyanogen bromide to obtain the title compound as white crystals. The yield was 63% of theory. The product was identified by its NMR spectrum as well as by the absorption of the cyanato group at 2260 cm-1 and the absence of phenolic hydroxy absorption in the IR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([OH:28])=O)[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1.Cl.CN.C[CH2:41][N:42]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([NH:42][CH3:41])=[O:28])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CN1C(=O)CC(c2cc(F)ccc2C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg, 0.13 mmol) prepared in example 146d, Methylamine hydrochloride (11 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (69 mg, 0.533 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-(methylamino-carbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (29 mg as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH3:35]>>[Cl:1][C:2]1[C:3]([C:12]([N:14]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[C:24]([NH2:26])=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5]([NH2:35])=[N:6][CH:7]=1
Reactant: N
Reactant: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(S(C)(=O)=O)ncc2Cl)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(N)ncc2Cl)c1

Procedure:
The title compound was prepared from the sulfone of example 248, using the method from example 244 and ammonia as the amine, to return the title compound as a foam, 22 mg, (12%)
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([N:18]4[CH2:23][CH2:22][CH:21]([C:24](OCC)=[O:25])[CH2:20][CH2:19]4)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[CH:11]1[C:12]2[C:13]3([CH2:16][N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1CCN(C(=O)C23CC(c4ccccc42)c2ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of ethyl 1-(9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-piperidine carboxylate (33.0 g, 88.4 mmol) in tetrahydrofuran (50 mL) was added dropwise to a suspension of lithium aluminum hydride (4.70 g, 123.8 mmol) in tetrahydrofuran (70 mL) held at reflux temperature. Upon complete addition, the mixture was held at reflux for 2 h, then was cooled to 0° C. and treated sequentially with 10% aqueous sodium hydroxide (4.7 mL), water (4.7 mL) and 10% aqueous sodium hydroxide (14.1 mL). The resulting white slurry was stirred for 30 minutes, treated with diatomaceous earth (25 g) and filtered through a pad of diatomaceous earth. The filter cake was washed with tetrahydrofuran/methanol (20:1, 2×200 mL). The filtrate was evaporated to give the title compound as a tan solid (23.5 g, 77.0 mmol, 87%) 1H NMR (d6-DMSO): δ7.25 (m, 2H), 7.18 (m, 2H), 4.38 (t, J=5.2 Hz, 1H, CH2OH), 4.29 (s, 1H, H--C(10)), 3.32 (s, 2H, CH2N), 3.21 (m, 2H, CH2OH), 2.97 (d, J=11.2 Hz, 2H, eq-H--C(2')), 2.44 (s, 2H, H--C(11)), 2.14 (dd, J=11.2, 11.2 Hz, ax-H--C(2')), 1.58 (d, J=11.0 Hz, eq-H--C(3')), 1.34 (m, 1H, H--C(4')), 1.10 (ddd, J=3.5, 11.0, 11.2 Hz, 2H, ax-H--C(3')).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[BH4-].[Na+]>C1COCC1>[F:4][C:3]([F:5])([F:6])[CH2:2][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: Oc1ccc(C(Cl)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1-chloro-2,2,2-trifluoroethyl)phenol (3.60 g, 17.1 mmol) in THF was added sodium borohydride (0.903 ml, 25.6 mmol) in one portion. The reaction was stirred at RT for 18 h, and then quenched with MeOH. The resulting mixture was concentrated and diluted with EtOAc. After washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum to afford 4-(2,2,2-trifluoroethyl)phenol as a colorless oil. MS m/z: 175(M−1).
Reaction SMILES: Cl.[C:2]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][NH:9][CH2:8]1)([O:4][CH2:5][CH3:6])=[O:3].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([N:9]1[CH2:10][CH2:11][C:12](=[O:13])[CH:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:8]1)=[O:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C1CNCCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C1CN(C(=O)C(C)(C)C)CCC1=O

Procedure:
To a mixture of 2.0 g of 3-carbethoxy-4-piperidone hydrochloride and 20 ml of 1M sodium carbonate is cooled in an ice bath and rapidly treated with 1.3 ml of trimethylacetyl chloride. Stirring is continued in the cold for 1.5 hours. The reaction mixture is filtered and the collected solid washed with water, air dried and then dried at 56° C. for 1.25 hours under high vacuum to afford 1.4 g of the desired product as a colorless solid, m.p. 46°-50° C.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[F:24][CH:25]([F:49])[C:26]1[O:30][C:29]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([C:37]3[S:38][C:39]([C:43]([O:45]CC)=[O:44])=[C:40]([CH3:42])[N:41]=3)[C:33]2=[O:48])=[CH:28][CH:27]=1>>[F:49][CH:25]([F:24])[C:26]1[O:30][C:29]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([C:37]3[S:38][C:39]([C:43]([OH:45])=[O:44])=[C:40]([CH3:42])[N:41]=3)[C:33]2=[O:48])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)sc1C(=O)O
Yield: 58 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-((5-(difluoromethyl)furan-2-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 58% yield: MS (ES+) in 358.2 (M+1).
Reaction SMILES: C[C:2]1([CH3:9])[CH:7](O)[C:5](=[O:6])[O:4]C1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21]C(C=CC(Cl)=O)=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:9]([CH:2]=[CH:7][C:5]([OH:4])=[O:6])=[CH:14][CH:13]=1
Reactant: CC1(C)COC(=O)C1O
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 92.6 %

Procedure:
16.3 g of <R>-pantolactone (0.125 mol) and 28 g of 4-methoxycinnamic acid chloride (about 0.14 mol) are placed in 170 ml of CH2Cl2 while gassing with argon in a 350 ml 4-necked sulphonation flask provided with a thermometer, a reflux condenser, a magnetic stirrer as well as a 20 ml dropping funnel. A solution of 11 g (0.139 mol) of pyridine in 30 ml of CH2Cl2 is now added dropwise within 30 minutes, whereby the temperature rises slowly. The reaction mixture is finally heated to reflux temperature for 3 hours. The reaction mixture is washed with 150 ml of water, 2× with 40 ml of 5% HCl, 2× with 40 ml of 5% NaHCO3 and 1× with 100 ml of water. The organic phase is separated and dried over Na2SO4. The solvent is removed on a rotary evaporator. The thus-obtained crude product is recrystallized from 100 ml of ethyl acetate/hexane (60:100). There are obtained 33.6 g of white crystals of the <R>-pantolactone ester of p-methoxycinnamic acid (yield 92.6%).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:69]([NH2:73])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:73][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC(C)(C)C)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl)amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and t-butylamine (9.54 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.4 mg, 52%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2
Reactant: [H][H]
Reactant: FC(F)(F)c1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CC2c3ccccc3CCc3ccccc32)c1
Reaction time: 17 h

Procedure:
Add 5-(3-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.145 g, 0.41 mmol), to a mixture of 10% Pd/C (0.04 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 352 (M+); GC retention time=7.11 min.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH3:28][O:29][C:30]1[CH:35]=C(F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CS(C)=O.CCOC(C)=O>[CH3:28][O:29][C:30]1[CH:35]=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:13][CH2:12]2)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(CN3CCCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
1,1-dimethylethyl 4-(1-piperidinylmethyl)-1-piperidinecarboxylate (1.25 g, 4.43 mmol) in DCM (40 mL) was cooled with an ice/H2O bath. TFA (8.80 mL, 115 mmol) was added dropwise via pipette. Upon completion by TLC the reaction was quenched with 1N NaOH (115 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated. The combined aqueous layer was treated with 1N NaOH, extracted with DCE/iso-propanol (4:1), dried (MgSO4) and concentrated. The crude material was added to 5-fluoro-2-nitrophenyl methyl ether (Example 22, step A) (0.833 g, 4.87 mmol) and K2CO3 (0.992 g, 7.17 mmol) in DMSO (15 mL) and stirred at rt overnight. Upon completion by TLC, the reaction was diluted with EtOAc (250 mL), washed with H2O (three times), dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound (0.890 g, 2.66 mmol, 60% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.14 (m, 2H), 1.30-1.41 (m, 2H), 1.42-1.50 (m, 4H), 1.72-1.83 (m, 3H), 2.07 (d, J=7.0 Hz, 2H), 2.27 (br. s., 4H), 2.93 (td, J=12.7, 2.2 Hz, 2H), 3.88 (s, 3H), 4.00 (d, J=13.6 Hz, 2H), 6.45 (d, J=2.6 Hz, 1H), 6.55 (dd, J=9.5, 2.6 Hz, 1H), 7.85 (d, J=9.5 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[NH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][NH:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of tert-butyl 3-(chloromethyl)benzoate (25.3 g) in N,N-dimethylformamide (250 mL) were added tert-butyl glycinate hydrochloride (37.4 g) and potassium carbonate (61.7 g), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (23.0 g).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[N:11]1[N:15]2[CH2:16][CH2:17][CH2:18][NH:19][C:14]2=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:5]([N:19]1[CH2:18][CH2:17][CH2:16][N:15]2[N:11]=[CH:12][CH:13]=[C:14]12)=[O:7]
Reactant: c1cc2n(n1)CCCN2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: O=CN1CCCn2nccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (0.153 ml) was added formic acid (0.077 ml) at 15°-20° C. The mixture was stirred at ambient temperature for 30 minutes. To this solution was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (100 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to a mixture of dichloromethane and aqueous sodium bicarbonate solution. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give 4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (79.9 mg).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1

Procedure:
A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 121.0 g (0.45 mole) of cis-9-octadecenol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue recrystallized from hexane to give 5-(cis-9-octadecen-1-yloxy)-2-furoic acid.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH:8](OCC)(OCC)[O:9][CH2:10][CH3:11].C(OC(=O)C)(=O)C>>[CH2:10]([O:9][CH:8]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(C)=O

Procedure:
From acetylacetone (20 g, 0.20 mol), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 19.3 g, 62%; bp=95°-110° C. at 0.3 mm Hg; NMR (CDCl3) δ 1.3-1.6 (t, 3H), 2.4 (d, 6H), 4.3-4.5 (q, 2H), 7.8 (d, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.F[P-](F)(F)(F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:30][O:29][N:20]([CH3:24])[C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
A mixture of 1H-indole-2-carboxylic acid (from Aldrich, 2.5 g, 16 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.6 g, 20 mmol) and triethylamine (11 mL, 78 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (2.0 g, 20 mmol) was added and the resulting suspension was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated and purified on silica gel (eluting with 0-50% EtOAc in hexane) to give the desired product (2.7 g, 85%). LCMS calculated for C11H13N2O2(M+H)+: m/z=205.1. Found: 205.1.
Reaction SMILES: [C:1]([CH2:5][CH:6]([F:8])[F:7])([F:4])([F:3])[F:2].[Cl:9]Cl>>[C:1]([CH2:5][C:6]([Cl:9])([F:8])[F:7])([F:4])([F:3])[F:2]
Reactant: FC(F)CC(F)(F)F
Reactant: ClCl
Product: FC(F)(F)CC(F)(F)Cl
Temperature: 0 °C

Procedure:
The reactor described above was cooled and maintained at about 0° C. during the photochlorination reaction. Initially, the reactor was purged of air using nitrogen. Chlorine gas was then introduced to displace the nitrogen. Thereafter, 335 g (2.5 mol) of CF3CH2CHF2 (HFC-245fa) was charged to the reactor. A total of 208 g (2.9 mol) of chlorine gas was bubbled into the CF3CH2CHF2 over a period of about 24 hours while the reactants were being irradiated. At the end of the 24 hour period, GC analysis indicated a 96% conversion of HFC-245fa (retention time 1.9 min) to the desired product HCFC-235fa (retention time 2.1 min). The reaction mixture was washed with 100 mL of a cooled (about 2° C.) solution of aqueous sodium bisulfite (10 wt. %) and distilled (boiling point=26-28° C.) to afford 383 g CF3CH2CF2Cl (yield, 91%). Absent cooling of the wash solution, loss of product by vaporization has been observed due to a slight exotherm during the washing step. No multichlorinated products were detected.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18]
Reactant: COCCBr
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Yield: 89.9 %

Procedure:
A solution of 5-hydroxy-1-(oxan-2-yl)-1H-indazole-3-carbaldehyde (120 mg, 0.49 mmol, 1.00 equiv), Cs2CO3 (180 mg, 0.55 mmol, 2.00 equiv) and 1-bromo-2-methoxyethane (500 mg, 3.60 mmol, 3.00 equiv) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 10 h. The reaction was diluted with 50 mL of ethyl acetate and then washed with 4×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum to give 134 mg (90%) of (R/S) 5-(2-methoxyethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a yellow oil. LCMS (method D, ESI): RT=1.48 min, m/z=305.1 [M+H]+.