Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:53]6[CH2:54][CH2:55][N:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51][CH2:52]6)[CH:41]=5)[CH:34]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (1.85 g, 2.80 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (1.055 g, 5.61 mmol) were dissolved in 1,2-dichloroethane (30 mL) and acetic acid (0.177 ml, 3.08 mmol) was added. The mixture was stirred for 30 minutes and then MP-Triacetoxyborohydride (3.61 g, 8.41 mmol) was added. The mixture was stirred overnight. It was then filtered through a glass fiber filter paper and washed 2× with 20 mL of DCE. The solvent was evaporated and the residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified on a Combiflash on an 80 g silica column eluted with 0-10% MeOH/CH2Cl2. Product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl 4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-methyl-3-biphenylyl)methyl]-1-piperazinecarboxylate (1.8 g, 2.140 mmol, 76% yield) as a white solid. LC-MS m/z 830 (M+H)+, 0.86 min (ret time).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:31][CH2:30][CH2:28][OH:29])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCO
Reactant: Clc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Solvent: CCOC(C)=O
Product: OCCNc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 73 %

Procedure:
A mixture of 130 mg of 6-chloro-N-(4-phenoxyphenyl)pyridin-2-amine in 214 mg of ethanolamine was filled in a screw cap vial and was treated analogously to the method as set out in Example 16b, but using for flash column chromatography a solvent mixture of EtOAc:PE=1:1 instead of EtOAc:PE=3:1). 2-(6-(4-Phenoxyphenylamino)pyridin-2-ylamino)ethan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[C:12]([OH:15])(=[S:14])[CH3:13].Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>O>[C:12]([S:14][CH2:17][CH2:18][N:19]1[C:20](=[O:29])[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:24])(=[O:15])[CH3:13]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
0.855 kg (7.9M) Potassium-tert-butoxide is added in portions at -5° under nitrogen atmosphere to 4 1 dimethylformamide. A solution of 0.6 kg (7.9M) thioacetic acid in 2 1 dimethylformamide is added in a steady stream at such a rate that the temperature can be maintained between -5° and 0° . The reaction mixture is then stirred for 1 hour at -5° . 2.0 kg (7.9M) N-(2-bromoethyl)phthalimide in 4 1 dimethylformamide is added to the reaction mixture at such a rate that the temperature does not exceed 5° and the reaction mixture is stirred for 2 hours. 40 1 of water cooled at 5°-10° are added which raises the reaction temperature to 20° . The reaction mixture is stirred overnight at room temperature and filtered. The crude product is washed with water and dried. M.P. 112°-114°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][CH2:2][CH2:3][O:4][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
10.0 g (corresponding to 80.0 mmol) of 2-bromoethanol and 10.9 g (corresponding to 160 mmol) of imidazole were dissolved in 100 mL of N,N-dimethylformamide (DMF), and cooled to 0° C. Then, 12.1 g (corresponding to 80.0 mmol) of t-butyldimethylchlorosilane (TBDMSCl) was added thereto. After the reaction mixture was stirred at room temperature for 3 hours, a saturated aqueous sodium hydrogencarbonate solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure (120° C., 100 mmHg), to obtain 14.5 g (corresponding to 60.6 mmol) of 1-bromo-2-(t-butyldimethylsiloxy)ethane (FIG. 9, Step 3).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:22][C:9]1[C:10]([NH2:20])=[N:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:21])=[CH:2][CH:3]=2)[N:8]=1
Reactant: Cc1ccc(-c2ncc(N)nc2-c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-di-p-tolylpyrazin-2-amine (step 2) (4.94 g, 17.94 mmol) in DMSO (40 ml) was treated with N-bromosuccinimide (3.19 g, 17.94 mmol). The reaction mixture was stirred at room temperature for 2 hours to give a beige coloured suspension. The suspension was diluted with water (700 ml) and the pH was adjusted to pH 8-9 using a sat. NaHCO3 solution. The suspension was filtered, washed with water (×3) and dried under vacuum to afford the titled compound as a beige coloured solid;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12]>C(O)C>[F:12][C:11]([F:14])([F:13])[C:10]1[N:1]=[C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: Nc1cnccn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: FC(F)(F)c1cn2ccncc2n1
Yield: 12.3 %

Procedure:
2-Aminopyrazine (12.5 g, 0.13 mol) and 3-bromo-1,1,1-trifluoro-propan-2-one (27.6 g, 0.14 mol) in ethanol (150 ml) was heated at reflux for 24 hours. A further portion of 3-bromo-1,1,1-trifluoro-propan-2-one (2.51 g, 14 mmol) was added and the mixture was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (30 ml). Solid sodium hydrogen carbonate was added to bring the pH to 8 and the solution was extracted with dichloromethane (×3). The combined organic layers were washed with water (20 ml) dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 2:98 to 4:96). The material isolated was further purified by chromatography on silica gel using methanol in dichloromethane as eluant (2:98). The material isolated was recrystallised from ethyl acetate/hexane to give the title compound as an orange brown solid (3 g).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].CCN(CC)CC.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]2[CH3:14])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CC1=CCCC(C)(C)C1C(=O)CC(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.6 %

Procedure:
To a solution of 3-hydroxy-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-butanone (1.00 g, 92% pure, 4.38 mmol), DMAP (100 mg), and NEt3 (1.0 ml, 7.2 mmol) in CH2Cl2 (20 ml) was added, at 0° C., tosylchloride (2.02 g, 10.56 mmol). The reaction medium was stirred at room temperature for 4 days. Then, the mixture was acidified with concentrated HCl and extracted twice with ether and washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl. Finally, the organic phases were dried over Na2SO4, concentrated at 50-60°/0.03 mbar). 0.76 g of product were thus obtained (yield: 50%).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:23][C:24]([Cl:34])([O:26][C:27](=O)[O:28]C(Cl)(Cl)Cl)[Cl:25]>C(Cl)Cl>[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][N:13]([C:27]([O:26][C:24]([Cl:34])([Cl:25])[Cl:23])=[O:28])[CH2:12][CH2:11]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(Cl)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
DIPEA (105 g, 0.81 mol) was added to a 0° C. solution of tert-butyl piperazine-1-carboxylate (25.0 g, 0.134 mol) in DCM (250 mL), followed by the addition of triphosgene (92 g, 0.27 mol) in portions over a 40 minute time period. The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs, filtered and concentrated to afford 1-tert-butyl 4-trichloromethyl piperazine-1,4-dicarboxylate (50 g) as an oil.
Reaction SMILES: O.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][S:10][N:11]=[C:7]2[CH:6]=1)([O-])=O>C1COCC1.[Zn]>[N:9]1[S:10][N:11]=[C:7]2[CH:6]=[C:5]([NH2:2])[CH:13]=[CH:12][C:8]=12
Reactant: O=[N+]([O-])c1ccc2nsnc2c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2nsnc2c1
Yield: 47.9 %

Procedure:
To a suspension of MoCl5 (8 g) in 50 ml of THF was added 10 ml of H2O and followed by the addition of Zn dust (3 g) 5 minutes later. 5-Nitrobenzo-2,1,3-thiadiazole (1.0 g) was then added to this mixture and the resulting reaction mixture was kept under reflux for 20 minutes. Benzo[1,2,5]thiadiazol-5-ylamine (0.4 g) was isolated by filtration and purified by column chromatography to be used in the next step.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O-])(O)=O.[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1>CCO>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:2]=[CH:3][N:17]=2)[CH:16]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In step 13-1, chloracetaldehyde (55% in water, 0.27 mL, 4.5 mmol) and NaHCO3 (143 mg, 1.7 mmol) were added to a solution of 5-bromopyridin-2-amine (173 mg, 1 mmol) in EtOH (7 mL). The mixture was heated to reflux and continued overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. Dichloromethane was added to extract the residue. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and evaporated to give the crude product. The crude was purified column chromatography (Silica gel, EtOAc/Hexane, gradient) to give 6-bromoimidazo[1,2-a]pyridine (13-1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1>C(Cl)Cl>[CH3:27][O:26][C:25]1[CH:24]=[C:23]2[C:18](=[CH:17][C:16]=1[O:15][CH3:14])[CH:19]=[C:20]([C:5](=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:21]=[CH:22]2
Reactant: CCCCCCC(=O)Cl
Reactant: COc1cc2ccccc2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (2.66 g) was added to a solution of: heptanoylchloride (3.1 ml) and 2,3-dimethoxynaphthalene (3.76 g) in methylene chloride (50 ml) at 0° C. The reaction mixture was stirred at room temperature overnight and then worked up as described in example 3(a). The crude product was recrystallized from ethanol. Yield: 2.8 g, melting point 77-78° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@@H:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6](=[O:20])[NH:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:10]=2[CH:9]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:17][N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([NH:7][C:6]([C@H:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:4][CH2:3][C:1]3[NH:31][N:30]=[N:29][N:2]=3)=[O:20])[CH:19]=[CH:18][C:11]=2[CH2:12][CH2:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCc2ccc(NC(=O)[C@@H](CCC#N)NC(=O)OC(C)(C)C)cc2CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2ccc(NC(=O)[C@@H](CCc3nnn[nH]3)NC(=O)OC(C)(C)C)cc2CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
200 mg (0.52 mmol) tert.butyl(R)-[3-cyano-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]carbamate are placed in 1 ml DMF and combined with 80 mg (1.23 mmol) sodium azide and 66 mg (1.23 mmol) ammonium chloride. The reaction mixture is stirred overnight at 100° C., then acidified with TFA and separated using RP material (eluant: water/acetonitrile 95:5=>5:95).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@@](C)(N)CO)C3)CC1

Procedure:
The mixture of (R)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (46.6 mg, 0.000121 mol) (from isomer 4) and lithium hydroxide (31.8 mg, 0.00133 mol) in ethanol (0.77 mL, 0.013 mol) and water (0.26 mL, 0.014 mol) was heated to reflux for overnight. LCMS showed starting material was consumed and peak Rf=1.66 min left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous layer was extensively extracted with dichloromethane and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product. (15.7 mg, 36% yield). LCMS 360.43 ([M+1], 100%). NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.07 (s, 3H), 1.09-1.54 (m, 6H), 1.79-1.87 (m, 3H), 2.04 (m, 1H), 2.15 (m, 2H), 2.53 (dd, J=15.5, 12.3 Hz, 1H), 2.72-2.86 (m, 3H), 3.46 (d, J=11.0 Hz, 1H), 3.55 (d, J=11.0 Hz, 1H), 4.07 (m, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.3, 2.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH2:7][S:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl>[NH2:7][S:8]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)CCCC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 27 %

Procedure:
Cs2CO3 (0.51 eq) was added to a solution of 4-(aminosulfonyl)butanoic acid (1 M) in DMF. After 1 h, benzyl bromide (1 eq) was introduced and the reaction left to stir overnight before diluting with DCM and filtering. The filtered liquor was concentrated in vacuo, the residue taken up in DCM and washed with saturated aqueous NaHCO3, water and brine, before being dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with Et2O afforded the title compound as a white solid (27%). (ES+) m/z 280 (M+Na)+
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][CH:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:33]([F:35])[F:34])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][CH:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:33]([F:35])[F:34])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)F)cc1
Yield: 83.5 %

Procedure:
TFA (5.3 mL) was added to a stirred solution of N-(5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-1-tert-butoxycarbonyl-L-prolinamide (0.626 g, 1.20 mmol) in CH2Cl2 (5.3 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo to give N-(5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-L-prolinamide (0.439 g) as a foam; MS m/z=438.4.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[O:12].C(N(CC)CC)C>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[C:13]([O:20][CH3:21])([O:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: COC(=O)C(OC)(OC)C(=O)Cl
Reactant: Cc1cc(Br)ccc1N
Solvent: CCN(CC)CC
Product: COC(=O)C(OC)(OC)C(=O)Nc1ccc(Br)cc1C
Yield: 50 %

Procedure:
4-Bromo-2-methylaniline (2.83 grams, 0.01 mole), methyl chlorocarbonyl(dimethoxy)acetate (2.99 grams, 0.01 mole), prepared in Part A, and triethylamine (1.54 grams, 0.015 mole) were reacted in a manner similar to the procedure described in Example I to give 1.73 grams (0.005 mole) of methyl 3-[(4-bromo-2-methylphenyl)amino]-2,2-dimethoxy-3-oxopropanoate having a melting point of 99° C.-103° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:12][CH3:13])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=C(O)CS
Reactant: CCC(O)c1cc2c(cc1C)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 90.2 %

Procedure:
2.27 g of 1-(6-methyl-1,3-benzodioxol-5-yl)-1-propanol, 0.1 g of p-toluenesulfonic acid and 1.52 g of mercaptoacetic acid were dissolved in 80 ml of benzene to obtain a solution. This solution was heated under reflux for 12 hours, while removing generated water. The reaction mixture was poured into water. The aqueous layer was basified and washed with ether. The aqueous layer was acidified and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated in a vacuum to obtain a pale yellow solid. This solid was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.83 g of the title compound as a white crystal.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[CH2:1]([C@@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CCO)Cc1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCO)Cc1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (R)-2-benzyl-4hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (R)-1-benzyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:12][N:11]2[CH:4]([CH2:5][CH:6]3[CH:10]2[CH2:9][N:8](C(OCC)=O)[CH2:7]3)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Ba+2]>O>[OH:1][CH:2]1[CH2:12][N:11]2[CH:4]([CH2:5][CH:6]3[CH:10]2[CH2:9][NH:8][CH2:7]3)[CH2:3]1
Reactant: CCOC(=O)N1CC2CC3CC(O)CN3C2C1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [K+]
Solvent: O
Product: OC1CC2CC3CNCC3N2C1

Procedure:
8 g (33.3 mmol) of ethyl 10-hydroxy-1,4-diazatricyclo[6.3.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 21 g of Ba(OH)2. 8H2O in 150 ml of water. The mixture is saturated with potassium carbonate, barium carbonate is filtered off with suction and the filtrate is extracted ten times using 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([F:30])=[C:26](F)[CH:27]=3)[C:22](=[O:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20]2)[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:26]1[CH:27]=[C:28]3[C:23]([C:22](=[O:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20][N:19]3[CH:16]3[CH2:18][CH2:17]3)=[CH:24][C:25]=1[F:30])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC12CNCCC1C2
Product: CC(C)(C)OC(=O)NC12CC1CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 64.7 %

Procedure:
According to the procedure of Example 34A, 1-tertbutoxycarbonylamino-3-azabicyclo[4.1.0]heptane (270.0 mg, 1.27 mmol) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (275.6 mg, 1.03 mmol) were reacted to generate the title compound (304.2 mg, 0.666 mmol, 65%).