Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:45][CH2:44][C:17]([CH3:46])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:43])[O:24][C:25]2[C:30]([CH2:31][O:32][CH2:33]3)=[CH:29][C:28]([F:42])=[CH:27][CH:26]=2)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:46])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:43])[O:24][C:25]2[C:30]([CH2:31][O:32][CH2:33]3)=[CH:29][C:28]([F:42])=[CH:27][CH:26]=2)[CH2:44][CH2:45]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1COC3
Reaction time: 3 h
Yield: 12 %

Procedure:
To a solution of ethyl (2S)-2-(tert-butoxy)-2-[(20S)-15-fluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17-heptaen-3-yl]acetate (36.5 mg, 0.057 mmol) in Methanol (3 mL) was added sodium hydroxide/1N (0.285 mL, 0.285 mmol) and the resulting solution was refluxed. After 3 h, The mixture was cooled and concentrated. The residue was purified by prep HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-15-fluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17-heptaen-3-yl]acetic acid (4.2 mg, 11.31% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.13 (dd, J=9.0, 2.8 Hz, 1H), 7.06-6.89 (m, 2H), 6.49 (s, 1H), 5.57 (s, 1H), 4.87 (d, J=12.5 Hz, 1H), 4.69-4.45 (m, 4H), 4.32 (t, J=11.6 Hz, 1H), 3.70-3.19 (m, 5H), 2.80 (br. s., 1H), 2.49-2.44 (m, 3H), 1.88 (d, J=14.3 Hz, 2H), 1.74-1.46 (m, 8H), 1.22-1.05 (m, 15H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[C:3]1=[O:29].[C:30](OC(=O)C)(=[O:32])[CH3:31].CO>CN(C)C1C=CN=CC=1.ClCCl>[C:30]([N:11]1[C:8]2=[N:9][C:10]3[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH3:20])[C:5](=[O:14])[C:6]=3[N:7]2[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: C[C@H](CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O[Si](C)(C)C(C)(C)C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a stirring mixture of (R)-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (280 mg, 0.65 mmol) and p-dimethylaminopyridine (160 mg, 1.30 mmol) in dichloromethane (10 ml) was added acetic anhydride (100 mg, 0.98 mmol). After stirring at room temperature for 2 hours, the reaction mixture was treated with methanol. After concentration under reduced pressure, the residue was purified by column chromatography on silica gel eluting with ethyl acetate to provide (R)-8-acetyl-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 67% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:39])[N:24]=[C:23](C2C=CC=CC=2Cl)[C:22]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=2[N:20]([CH3:37])[C:19]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:39])[N:24]=[CH:23][C:22]3[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:21]=3[N:20]([CH3:37])[C:19]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=Cc2cc(Cl)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-F), the title compound was prepared as a white solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH2:10])[CH2:5][CH:4]1[CH:11]=[CH2:12])=[CH2:2].[Cl:13][SiH:14]([Cl:16])[Cl:15]>>[Cl:13][Si:14]([Cl:16])([Cl:15])[CH2:2][CH2:1][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][Si:14]([Cl:16])([Cl:15])[Cl:13])[CH2:5][CH:4]1[CH2:11][CH2:12][Si:14]([Cl:16])([Cl:15])[Cl:13]
Reactant: C=CC1CCC(C=C)C(C=C)C1
Reactant: Cl[SiH](Cl)Cl
Product: Cl[Si](Cl)(Cl)CCC1CCC(CC[Si](Cl)(Cl)Cl)C(CC[Si](Cl)(Cl)Cl)C1
Temperature: 80 °C

Procedure:
To 162 g of 1,2,4-trivinylcyclohexane there are added 4 mg of Pt in the form of a platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex, the so-called Karstedt catalyst, which corresponds to the catalyst as prepared in accordance with U.S. Pat. No. 3,775,452 (issued on Nov. 27, 1973, Bruce D. Karstedt, General Electric Co.), and the mixture is heated to about 80° C. A total of 450 g of trichlorosilane are added dropwise over a period of about 2 hours, the temperature of the liquid phase slowly rising under reflux and then falling again toward the end of the reaction. The batch is boiled at reflux for an additional 1 hour and the volatile constituents are distilled off up to 100° C. at 3 mPa.s. The title substance is obtained in virtually quantitative yield (564 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][F:11].Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:11])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:26][CH2:27]1
Reactant: CCC1SC(=O)NN=C1c1ccc(OCF)c(OC)c1
Reactant: ClCCCN1CCOCC1
Product: CCC1SC(=O)N(CCCN2CCOCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
In analogy to Example 1, by reacting 5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4thiadiazin-2-one with 1-chloro-3-morpholinopropane, 3-morpholinopropyl-5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1.[NH:44]1[C:48]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:46]=[N:45]1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]2[N:31]([C:27]([CH2:26][N:44]3[C:48]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:46]=[N:45]3)=[C:28]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:29]=2)[CH:32]=1
Reactant: COC(=O)c1ncn[nH]1
Reactant: Fc1ccc(-c2nc3ccc(F)cn3c2CCl)cc1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and methyl 1H-1,2,4-triazole-5-carboxylate. The two isomers were separated by silica gel chromatography eluted with 20% acetone to flash out the less polar spot and 50% acetone to flash out the second spot (more polar spot). m/e− 370 for C18H14F2N5O2 (M+H)−.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([Cl:14])=[O:4]
Reactant: CCCCC(C)(CC)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCC(C)(CC)C(=O)Cl
Yield: 90.6 %

Procedure:
316 gm (2moles) of 2-methyl-2-ethyl-hexanoic acid were heated to boiling with 357 gm (3 moles) of thionyl chloride under agitation until the evolution of gas had ended. The surplus thionyl chloride was distilled off and the residue was fractionated in vacuo. 320 gm (90% of theory) of 2-methyl-2-ethyl-hexanoyl chloride of b.p. 78° C. at 13 mmHg were obtained.
Reaction SMILES: [CH2:1]1[CH:6]=[CH:5][O:4][CH:3]([CH:7]=O)[CH2:2]1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[CH3:10][C:9]([N:13]=[CH:7][CH:3]1[CH2:2][CH2:1][CH:6]=[CH:5][O:4]1)([CH3:12])[CH3:11]
Reactant: O=CC1CCC=CO1
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)N=CC1CCC=CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 323.0 g of acrolein dimer in 230 ml of anhydrous ethanol was added dropwise to a solution of 251 ml of t-butylamine in 250 ml of anhydrous ethanol at 25° C. over 2 hours. The reaction mixture was stirred at room temperature overnight. The solvents were stripped off on a rotary evaporator to leave 295.5 g of a yellow oil. This oil was vacuum distilled at 8 mm Hg to give 223 g of a colorless oil at 63°-67° C. and four fractions of colorless oil were collected as follows: 2.82 g at 45°-63° C., 181.27 g at 63°-66° C., 42.42 g at 66°-67° C. and 37.09 g at 67°-70° C., and were a mixture of isomers of the desired product.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH2:20][S:19][CH2:18][CH2:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[O:22]=[S:19]1[CH2:18][CH2:17][C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH2:20]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CSCC3
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CS(=O)CC3
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.3 g of 2,3,5,6,7,9-hexahydro2-phenylthiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in 200 mL of methanol, a solution of 0.8 g of sodium metaperiodate in 25 mL of water is added. The mixture is stirred at room temperature for 48 hours, then evaporated to dryness. The residue is washed with 50 mL of water, filtered, and dried in a vacuum oven at 80° overnight obtaining 2,3,5,6,7,9-hexahydro-8-oxo-2-phenylthiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 218°-220° (dec).
Reaction SMILES: C(C1C=CC(NC2C(F)=CN=C(NC3C=CC4OC(C(O)=O)CC=4C=3)N=2)=CC=1)(C)(C)C.[CH2:32]1[CH2:41][O:40][C:39]2[CH:38]=[CH:37][C:36]([NH:42][C:43]3[C:48]([F:49])=[CH:47][N:46]=[C:45]([NH:50][C:51]4[CH:52]=[CH:53][C:54]5[O:58][C:57]([C:59]([O:61]C)=[O:60])=[CH:56][C:55]=5[CH:63]=4)[N:44]=3)=[CH:35][C:34]=2[O:33]1.[Li+].[OH-]>>[CH2:32]1[CH2:41][O:40][C:39]2[CH:38]=[CH:37][C:36]([NH:42][C:43]3[C:48]([F:49])=[CH:47][N:46]=[C:45]([NH:50][C:51]4[CH:52]=[CH:53][C:54]5[O:58][C:57]([C:59]([OH:61])=[O:60])=[CH:56][C:55]=5[CH:63]=4)[N:44]=3)=[CH:35][C:34]=2[O:33]1
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1
Agent: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-(2,3-dihydro-2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine, N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and LiOH were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].B(F)(F)F.CCOCC.CO>C1COCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(CO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (1.82 g, 10.0 mmol) in anhydrous THF (50 ml) was added sodium borohydride (770 mg, 20.0 mmol) followed by boron trifluoride diethyl etherate (2.5 ml, 20 mmol) and the mixture stirred at ambient temperature under a nitrogen atmosphere for 2 h. MeOH was cautiously added until gas evolution had ceased and the mixture reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4) and reduced in vacuo to give 2-amino-3-nitrobenzyl alcohol (1.42 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@@H:32]1[CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH2:33][C@@H:32]1[CH2:36][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 85.4 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 0.740 g of potassium t-butoxide and 2.33 g of (R)-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.54 g (yield 85%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=1.O>CC(O)=O.OP(O)(O)=O>[Cl:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2oc3c(c2c1Cl)NC(c1csc(C(C)C)n1)CC3=O
Temperature: 25 °C
Yield: 108.4 %

Procedure:
10A (9.96 g, 26.43 mmol) was dissolved in AcOH (50 mL) and H3PO4 (50 mL). The solution was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The brown precipitates were collected by filtration and dried to give product 10B (10.8 g), which was used for the next step directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23].CN1CCOCC1.CCCP(=O)=O>O.CN1C(=O)CCC1>[CH3:21][S:22]([C:25]1[CH:30]=[C:29]([CH2:31][NH:32][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1cc(CN)ccn1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A 250 mL flask was charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (10.0 g, 33.9 mmol, 87.2 wt. %, 1.0 eq), (2-(methylsulfonyl)pyridin-4-yl)methanamine hydrochloride (8.54 g, 37.3 mmol, 97.3 wt. %, 1.10 eq), NMP (30 mL) and finally N-methylmorpholine (18.6 mL, 169.5 mmol, 5.0 eq). To the slurry was charged propylphosphonic anhydride (23.97 mL, 40.68 mmol, 50 wt. % solution in EtOAc, 1.2 eq). The batch was then heated to 60° C. and held at this temperature for 1 hour. Water (80 mL) was charged, and the batch was cooled to ambient temperature and held for 1 hour. The batch was filtered, the solid washed with water, and then oven dried under vacuum to afford the title compound as a light yellow solid, 12.7 g, >99.5 area % purity by HPLC, 88% yield.
Reaction SMILES: NC1C=C(S(N[C@H]2CC[C@H](C(OC)=O)CC2)(=O)=O)C=CC=1Cl.[N+:23]([C:26]1[CH:27]=[C:28]([S:33]([NH:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH2:38]2)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[CH3:32])([O-])=O>>[NH2:23][C:26]1[CH:27]=[C:28]([S:33]([NH:36][C@H:37]2[CH2:38][CH2:39][C@H:40]([C:43]([O:45][CH3:46])=[O:44])[CH2:41][CH2:42]2)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C)c([N+](=O)[O-])c2)CC1
Agent: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c(N)c2)CC1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C)c(N)c2)CC1

Procedure:
Methyl trans-4-(3-amino-4-methyl-phenylsulfonamido)cyclohexane-carboxylate was prepared by a method analogous to the method used to prepare Intermediate 10 using methyl trans-4-(3-nitro-4-methyl-phenylsulfonamido)cyclohexane-carboxylate (Intermediate 5) as the starting material. MS MH+ 327.2
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:9]([O:11]C(=O)C=O)[CH3:10]>C(O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:10][C:9]1=[O:11]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C=O
Solvent: CCO
Product: O=c1cnc2ccccc2[nH]1

Procedure:
Heat benzene-1,2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethyl ester (20 mL) in ethanol (100 mL) at 120° C. for 18 h. Cool, filter the resulting precipitate, and wash with dry ether to give 1H-quinoxalin-2-one (6.7 g). Dissolve 1H-quinoxalin-2-one in acetic acid (300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h. Filter the resulting crystals and wash with ether to afford 7-bromo-1H-quinoxalin-2-one (7.2 g). Reflux 7-bromo-1H-quinoxalin-2-one in POCl3 (30 mL) for 18 h. Remove POCl3 in vacuo, dissolve the product in 3:1 chloroform/isopropyl alcohol, and wash the organic phase with saturated sodium bicarbonate. Dry over sodium sulfate and purify by silica gel flash chromatography eluting with dichloromethane to 10% methanol/90% dichloromethane to afford the title compound as a yellow solid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).
Reaction SMILES: C([SnH2]CCCC)CCC.[CH2:10]([Sn:18](Cl)(Cl)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:19]([SnH2:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC[Sn](Cl)(Cl)CCCCCCCC
Agent: CCCC[SnH2]CCCC
Product: CCCCCCCC[SnH2]CCCCCCCC

Procedure:
The operating procedure followed was the same as that employed in Example 1 for the synthesis of dibutyltin dihydride, except that the starting material was dioctyltin dichloride.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][CH:23]=[C:22]([Cl:32])[CH:21]=3)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.[F-].[F-].[F-]>C1COCC1.C(OCC)C>[Cl:32][C:22]1[CH:21]=[C:20]2[C:25]([C:26]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[C:18]([C:16]([C:11]3[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=3)=[O:17])[NH:19]2)=[CH:24][CH:23]=1
Reactant: CCC(=O)Nc1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)[nH]c2cc(Cl)ccc12
Agent: CCCC[NH3+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(=O)Nc1c(C(=O)c2ncccc2CO)[nH]c2cc(Cl)ccc12
Reaction time: 4.5 h
Yield: 87.7 %

Procedure:
To a solution of 2-[(3-tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-6-chloro-3-(propionylamino)indole (step 5, 544 mg, 1.15 mmol) and acetic acid (0.20 ml, 3.50 mmol) in THF (30 ml) was added tetra(n-butylammonium)fluoride (1M in THF, 3.5 ml, 3.50 mmol) at 0° C. The mixture was stirred for 4.5 h at the same temperature and diluted with diethyl ether (200 ml). This solution was washed with saturated aqueous sodium bicarbonate (50 ml), water (50 ml×2), and dried (MgSO4). Removal of solvent gave a crystalline residue. Recrystallization from ethyl acetate afforded 361 mg (88%) of the title compound. m.p.: 198-199° C. IR (KBr) ν: 3250, 1663, 1624, 1607, 1578, 1541, 1472, 1352, 1211, 1178, 1153, 1074, 1045, 1013, 833, 808, 716 cm−1 1H-NMR (CDCl3) δ: 11.33 (1 H, br s), 10.74 (1 H, br s), 8.75 (1 H, dd, J=1.6, 4.8 Hz), 8.47 (1 H, d, J=9.1 Hz), 8.00 (1 H, dd, J=1.5, 7.7 Hz), 7.57 (1 H, dd, J=4.8, 7.7 Hz), 7.36 (1 H, d, J=1.8 Hz), 7.05 (1 H, dd, J=1.8 and 9.1 Hz), 4.87 (2 H, d, J=7.3 Hz), 4.00 (1 H, t, J=7.1 Hz), 2.62 (2 H, q, J=7.6 Hz), 1.36 (3 H, t, J=7.6 Hz).
Reaction SMILES: C([O:4][C@H:5]1[CH2:8][C@H:7]([C:9]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[CH2:13][CH2:12]2)=[O:10])[CH2:6]1)(=O)C.C1COCC1.O.O[Li].O>O>[CH:18]1([N:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:9]([C@H:7]3[CH2:8][C@H:5]([OH:4])[CH2:6]3)=[O:10])[CH2:12][CH2:13]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)O[C@H]1C[C@H](C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C([C@H]1C[C@H](O)C1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a stirred solution trans-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutyl acetate (50 mg, 0.17 mmol) in 5:1 THF/H2O (93 ml) at RT was added LiOH.H2O (8.5 mg, 0.2 mmol). The mixture was stirred at RT overnight, diluted with H2O and extracted with DCM. The organic layer was then dried (Na2SO4), filtered and concentrated at reduced pressure to yield the title compound as pale yellow oil (40 mg, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O-])=[O:14])=[CH:11][C:10]=1[CH:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].CO.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[C@@H:18]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:19][CH2:20][N:21]([CH:22]([CH3:23])[CH3:24])[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCC(c1ccccc1)c1cc(C(=O)[O-])ccc1OCc1ccccc1)C(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 gm (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl propyl)benzoate and 25 ml toluene was added under nitrogen atmosphere to a solution of 5.5 g Vitride in 50 ml toluene at 0° C. to 5° C. After stirring at room temperature for 5 hours, methanol was added drop wise at 0° C. to 5° C. After raising the temperature to room temperature, water and toluene was added and stirred for 30 minutes at 25° C. to 35° C. Layers were separated. Toluene layer after complete distillation afforded the title compound as (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl propyl)-phenyl]-methanol of formula (H).