Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[OH:1][C@@:2]([CH3:23])([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:4]
Reactant: COc1ccc(C[C@](C)(O)C(=O)Nc2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@](O)(Cc1ccc(O)cc1)C(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
(S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c) (0.20 g, 0.63 mmol) was dissolved in dry CH2Cl2 (20 mL). BBr3 (6 mL of 1.0 M CH2Cl2 solution) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in a ice bath and hydrolyzed by adding water (25 mL). EtOAc (50 mL) was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with hexanes/EtOAc (3/7 v/v) to afford a white solid product, (S)-2-hydroxy-N,3-bis(4-hydroxyphenyl)-2-methylpropanamide (6g), 0.12 g, 65.6% yield.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]([C:11]([O:13]C)=[O:12])=[N:9][CH:8]=[CH:7][N:6]=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[N:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1nccnc1Oc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nccnc1Oc1ccc(F)cc1F

Procedure:
A solution of 5.3 g (20 mmol) of methyl 2-(2,4-difluorophenoxy)-3-pyrazinecarboxylate in 50 ml of methanol is treated with 5.6 g (0.1 mol) of potassium hydroxide at room temperature for 2 hours. The reaction mixture is freed from the solvent under reduced pressure and the residue is taken up in distilled water. On acidification to pH 2-3, the 2-(2,4-difluorophenoxy)-3-pyrazinecarboxylic acid is precipitated from the solution.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10][CH2:9]2)=[C:4]([O:30][C:31]([F:34])([F:33])[F:32])[CH:3]=1.[NH3:35].O.[ClH:37]>CCO.CCOC(C)=O.[Cu].Cl[Cu]>[ClH:37].[ClH:37].[ClH:37].[NH2:35][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C@@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10][CH2:9]2)=[C:4]([O:30][C:31]([F:34])([F:33])[F:32])[CH:3]=1
Reactant: N
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](NCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: Cl[Cu]
Agent: [Cu]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCc3ccc(N)cc3OC(F)(F)F)CC2)nc2ccccc12

Procedure:
To a solution of cis-N2-[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step A of example 28 (1.5 g, 2.79 mmol) in EtOH (25 mL) were added copper powder (443 mg, 6.93 mmol), CuCl (690 mg, 2.79 mmol), and 28% aqueous NH3 (25 mL). The reaction mixture was stirred at reflux for 3.5 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a colorless oil. To a solution of above oil in EtOAc (4 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et2O (15 mL) was stirred at ambient tempareture for 1 hr. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine trihydrochloride (104 mg, 6%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
Under nitrogen atmosphere, 3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2 eq.) were added with THF (2 ml), and then further added dropwise with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 2 eq.) and 2.19 N toluene solution of diethyl azodicarboxylic acid (0.26 mL, 2 eq.). The resultant was stirred at room temperature for 12 hr under nitrogen atmosphere. The residues obtained after concentrating the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (white powder, 120 mg).
Reaction SMILES: ClC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.Cl[S:30]([C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35](S(C2C=CC=CC=2)(=O)=O)[C:34]=1[C:53]([O:55]CC)=O)(=[O:32])=[O:31].[NH:58]1CCOCC1.N1CCC1>>[N:7]1([S:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[NH:35][C:34]=2[C:53]([NH2:58])=[O:55])(=[O:31])=[O:32])[CH2:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(OC)ccc2n1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Agent: C1CNC1
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCC3)c2c1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine, the title compound was obtained. HRMS (ES) exact mass calculated for C13H16N3O4S (M+H+): 310.0856. Found 310.0877.
Reaction SMILES: [OH-].[Na+:2].[N:3]([C:16]1[CH:17]=[C:18]([C:23]([OH:26])=[CH:24][CH:25]=1)[C:19]([O:21]C)=[O:20])=[N:4][C:5]1[CH:6]=[C:7]([C:12]([OH:15])=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9]>>[Na+:2].[Na+:2].[N:3]([C:16]1[CH:17]=[C:18]([C:23]([OH:26])=[CH:24][CH:25]=1)[C:19]([O-:21])=[O:20])=[N:4][C:5]1[CH:6]=[C:7]([C:12]([OH:15])=[CH:13][CH:14]=1)[C:8]([O-:10])=[O:9]
Reactant: COC(=O)c1cc(N=Nc2ccc(O)c(C(=O)OC)c2)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1cc(N=Nc2ccc(O)c(C(=O)[O-])c2)ccc1O
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of sodium hydroxide (48 g, 1.2 mol in 800 ml of water) was charged compound 1c (80 g, 0.24 mol) at 25–30° C. The resulting dark black-red coloured solution was heated to mild reflux (reaction mixture temperature ˜85–90° C.) and was held for 90 minutes. This was then treated with activated carbon and refluxed further for 30 minutes. Then the reaction mixture was cooled to 45–50° C. and was filtered through a celite bed (prepared in water). The celite bed was washed with water (4×80 ml) and was mixed with the main filtrate. Further 240 ml of water was added to the combined filtrate and washings and cooled to 25–30° C. with efficient stirring. The pH of this resulting solution was adjusted to 6.0±0.05 with dropwise addition of 20% v/v aqueous acetic acid over 30–45 minutes. The resulting yellow slurry was cooled to 0–5° C. and stirred for 30 minutes to complete the crystallization. Compound 1d thus obtained was filtered and washed with water (2×160 ml) followed by isopropanol wash (2×40 ml). The wet cake obtained (107 g) was dried at 70° C. under reduced pressure (˜650 mm of Hg) for 16 hours to constant weight. The title compound 1d was obtained in 65% yield (55 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:8]([P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])[CH:7]=1.O[Li].O>C1COCC1.O>[CH2:27]([O:26][P:24]([C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][P:14]([O:16][CH:17]([CH3:18])[CH3:19])([O:20][CH:21]([CH3:22])[CH3:23])=[O:15])([O:29][CH2:30][CH3:31])=[O:25])[CH3:28]
Reactant: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1OCP(=O)(OC(C)C)OC(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)c1cc(CCC(=O)O)ccc1OCP(=O)(OC(C)C)OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
3-(3-Diethylphosphono-4-diisopropylphosphonomethoxyphenyl)propionic acid methyl ester (474 mg, 0.96 mmol) in 5 mL THF at 0° C. was added LiOH.H2O (60 mg, 1.43 mmol) in 1 mL H2O. The reaction mixture was stirred at 0° C. for 1 hr. THF was removed in vacuo and 5 mL 1N HCl was added. Aqueous phase was extracted with DCM (8×10 mL). Combined organic was dried over Na2SO4, concentrated to yield crude product 400 mg (yield 87%) as a clear oil. Electrospray mass spectrum: m/z 479.50 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:4][CH2:3]1.C(O)C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
0.46 g (0.95 mmol) of methyl 4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)benzoate is dissolved in 20 ml of tetrahydrofuran, 2 ml of ethanol and 1 ml of water, and 0.46 g (11 mmol) of lithium hydroxide monohydrate is then added. The reaction medium is refluxed for 15 hours, acidified with 2N hydrochloric acid solution and then extracted with ethyl acetate. The solid obtained is washed with a heptane/ethyl ether mixture (90/10) and then purified by chromatography (eluent: dichloromethane). An off-white powder is obtained (0.2 g; yield=45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(COC)OC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cccc(Cl)n2)c1
Temperature: 25 °C

Procedure:
A mixture of m-methoxy-phenylboronic acid (10 g, 65.8 mmol), 2,6-dichloropyridine (9.7 g, 65.8 mmol), potassium carbonate (27.3 g, 197.4 mmol), triphenylphosphine (2.07 g., 7.9 mmol), dimethoxyethane 250 mL and water 80 mL was prepared. Nitrogen was bubbled directly in the mixture for 20 minutes. Then palladium acetate was added (0.44 g, 2.0 mmol). Nitrogen was bubbled again in the mixture for another minutes. The mixture was heated to reflux under nitrogen overnight. The reaction mixture was cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified by silica column with up to 10% ethyl acetate in hexanes to gain 6.5 g colorless oil (45%).
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.[OH:13][C:14]1[C:15]([C:32](=O)[CH3:33])=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]2.O[CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:33][C:32]1[C:15]2=[C:16]3[C:20](=[CH:21][CH:22]=[C:14]2[O:13][CH2:36][CH2:37][N:38]=1)[N:19]([S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]3
Reactant: CC(=O)c1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Temperature: 43 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (73 mg, 0.43 mmol) was added to a solution of 1-[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethanone (Intermediate 23, 67 mg, 0.21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (0.14 g, 0.85 mmol) and triphenylphosphine (112 mg, 0.430 mmol) in DCM (5 mL). The mixture was heated at 43° C. for 1 hour and additional 1,1′-azobis(N,N-dimethylformamide) (0.030 g, 0.17 mmol) was added and the mixture was heated at 43° C. for an additional 2 hours. The mixture was cooled to room temperature and TFA (2.5 mL) was added and the mixture was stirred for 1 hour and evaporated. The residue was partitioned between DCM and 1 M NaOH. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 5% MeOH in DCM as the eluent to give 75 mg of 1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole. Acetic acid (132 mg, 2.20 mmol) was added to a solution of the 1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (75.0 mg, 0.22 mmol) in DCM (10 mL) and the mixture was allowed to stir for 10 minutes at room temperature before sodium triacetoxyborohydride (0.070 g, 0.33 mmol) was added all in one portion. The mixture was stirred for 30 minutes and transferred to a separation funnel and washed with 1 M NaOH and brine. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (5:94:1) as the eluent to give the title compound (28 mg) as a white solid. MS m/z 343 [M+H]+.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=1)(=[O:16])=[O:15])C.Cl>O.C1COCC1>[OH:31][CH:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][S:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:32])=[O:5])(=[O:16])=[O:15])=[CH:20][CH:21]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC(O)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)O)cc1
Reaction time: 16 h
Yield: 74.2 %

Procedure:
Lithium hydroxide (0.47 mL of a 0.5 N solution in H2O, 0.236 mmol) was added to a solution of the ester 11 (52 mg, 0.118 mmol) in THF (1.5 mL) at 23° C. The reaction mixture was stirred for 16 h, acidified with 1 N HCl and extracted with EtOAc. The organic portion was washed with brine (2×), dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 100% EtOAc) gave 36.2 mg (72%) of the free acid 12 as a light yellow, viscous oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH:17]([CH3:20])[CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[S:2]([O:19][CH2:18][CH:17]([O:16][C:15]1[CH:21]=[CH:22][C:12]([O:11][C:10]2[CH:23]=[CH:24][C:7]([Cl:6])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1)[CH3:20])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Product: CC(COS(C)(=O)=O)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
8.1 g (0.07 mol) of methanesulphonyl chloride are run, at about 10° C., into a solution of 19.5 g (0.07 mol) of (±)-2-[4-(4-chlorophenoxy)-phenoxy]-1-propanol (CRL 40 300) prepared as indicated in Example 27, in 35 ml of pyridine. The reaction mixture is stirred for 1 hour at ambient temperature and is poured onto ice. The insoluble matter is extracted with diethyl ether and the organic phase obtained is washed with dilute hydrochloric acid and dried, to give a white pasty residue after evaporation of the solvent. The solidification of this residue is petroleum ether gives 24 g of a white powder which is insoluble in water.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH:9]([CH3:18])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>[OH-].[OH-].[Pd+2].C(O)C>[CH3:18][CH:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:20][CH:19]=1)[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CC(CCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(CCN1CCOCC1)Oc1ccc(N)cc1

Procedure:
To 50 mL ethanol is added 28 g (0.1 mol) of 4-[3-(4-nitrophenoxy)butyl]morpholine and 0.5 g of Pd(OH)2. The mixture is hydrogenated at 30 psi. Monitor the reaction by thin-layer chromatography. Upon completion remove the catalyst by suction filtration through celite. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: N1C=CC=CC=1.[S:7](=[O:10])(=[O:9])=[O:8].[CH2:11]([OH:33])[C@H:12]1[O:17][C@H:16]([O:18][C@:19]2([CH2:28][OH:29])[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])[C@H:15]([OH:30])[C@@H:14]([OH:31])[C@@H:13]1[OH:32]>O>[CH2:11]([O:33][S:7]([OH:10])(=[O:9])=[O:8])[C@H:12]1[O:17][C@H:16]([O:18][C@:19]2([CH2:28][O:29][S:7]([OH:10])(=[O:9])=[O:8])[O:23][C@H:22]([CH2:24][O:25][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:21]([O:26][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:20]2[O:27][S:7]([OH:10])(=[O:9])=[O:8])[C@H:15]([O:30][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:14]([O:31][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:13]1[O:32][S:7]([OH:10])(=[O:9])=[O:8]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: O=S(=O)=O
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(O)OC[C@H]1O[C@@](COS(=O)(=O)O)(O[C@H]2O[C@H](COS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@H](OS(=O)(=O)O)[C@H]2OS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@@H]1OS(=O)(=O)O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
254.7 g (1.6 mol) of sulfur trioxide pyridine were slurried in 1300 ml of water-free pyridine. With stirring, 68.5 g (0.2 mol) of sucrose were added. The reaction mixture was heated to 65° C. and kept at this temperature for 240 minutes. As the reaction proceeded, the substance was separated as a thick flowing oil. When the reaction was terminated, the agitator was stopped, the pyridine phase was decanted, and the oily phase was dissolved in 600 ml of ion-exchanged water.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([Cl:40])[CH:42]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: Nc1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(Cl)c4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 3-chloroaniline (56 mg, 0.44 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (193 mg) as a yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)=O>CS(C)=O.C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][N:8]=[CH:13][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:16]=1)=[O:6]
Reactant: O=Cc1ccc(OCC(=O)O)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(C=NNC(=O)c2ccc(O)c(Cl)c2)c2ccccc12
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-1-yloxy) acetic acid (3 g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3×), brine, and dried over MgSO4. The volume was reduced to approximately 100 mL and placed in an ice-bath. The resulting solid was filtered and washed with cold ethyl acetate to afford {4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-yloxy}acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
After adding N,N-dimethylformamide (20 ml) to [1,4]diazepane-1-carboxylic acid benzyl ester (2 ml) under a nitrogen atmosphere, potassium carbonate (6.67 g) and 2-dimethylaminoethyl chloride (1.67 g) were added at room temperature. The reaction mixture was heated to 70° C. and stirred for 2 hours. It was then heated to 80° C. and stirred for 1 hour. Next, 2-dimethylaminoethyl chloride (420 mg) was further added and the reaction mixture was stirred for 2 hours. The reaction mixture was then cooled to room temperature. It was subsequently partitioned between ethyl acetate (100 ml) and saturated aqueous ammonium chloride (50 ml). The separated organic layer was washed with saturated aqueous ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the resultant residue was purified by silica gel column chromatography (FUJI SILYSIA NH, eluent; heptane:ethyl acetate=4:1). Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of 4-(2-dimethylaminoethyl)-[1,4]diazepane-1-carboxylic acid benzyl ester (724 mg, 24.5%) as a pale yellow oil.