Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.02 h
Yield: 64.9 %

Procedure:
3.0 g (13 mmol) of p-dibromobenzene was dissolved in 100 ml of anhydrous diethyl ether, and under room temperature and an argon stream, 8.0 ml (13 mmol) of 1.6M n-butyllithium (hexane solution) was gradually added dropwise, followed by stirring for 1 minute. Further, 2.8 g (14 mmol) of trimethyltin chloride was added, and refluxed at 50° C. for 2 hours. After the reaction, the reaction solution was cooled, saturated ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give 2.7 g of 4-bromophenyltrimethyltin as a colorless oil (yield 66%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[C:8]([C:12]4[C:16]5[S:17][CH:18]=[CH:19][C:15]=5[O:14][N:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(N2CCN(CCCOc3cccc(-c4noc5ccsc45)c3)CC2)cc1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 1-(4-fluorophenyl) piperazine and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (99:1). Combine the appropriate fractions and concentrate to give the title compound (0.44 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=438 m/e.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:14]([CH2:21][C:22]3[N:23]=[C:24]([CH2:27][CH2:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[CH2:36][CH2:35][CH2:34][NH:33][C:32]=5[N:31]=4)[S:25][CH:26]=3)[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:13]=2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>C1COCC1>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:14]([CH2:21][C:22]3[N:23]=[C:24]([CH2:27][CH2:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[CH2:36][CH2:35][CH2:34][NH:33][C:32]=5[N:31]=4)[S:25][CH:26]=3)[CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(Cc1csc(CCCc2ccc3c(n2)NCCC3)n1)c1cnc(-c2ccc(Cl)cc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(Cc1csc(CCCc2ccc3c(n2)NCCC3)n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 295.5 %

Procedure:
Ethyl 3-[2-(4-chlorophenyl)-1,3-thiazol-5-yl]-4-{2-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl )propyl]-1,3-thiazol-4-yl}butanoate hydrochloride (Scheme 3, Step 2), (180 mg, 0.281 mmol) was dissolved in THF. Upon cooling to 0° C., 0.84 mL LiOH (1M) was added and allowed to stir at room temperature overnight. The reaction was acidified to pH=1 with HCl and concentrated in vacuo. The residue was purified via reverse phase HPLC to yield the title compound (239 mg, 78%). 1H NMR (DMSO-d6) δ1.77–1.87 (m, 2H), 2.02–2.12 (m, 2H), 2.61–2.82 (m, 6H), 2.95–3.18 (m, 4H), 3.39–3.45 (m, 2H), 3.85–3.95 (m, 1H), 6.55 (d, 1H), 7.18 (s, 1H), 7.48–7.54 (m, 2H), 7.56 (d, 1H), 7.62 (s, 1H), 7.80–7.85 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](OCC)=[O:20])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:25]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH2:25])=[O:20])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: N
Reactant: CCOC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 60 °C

Procedure:
A mixture of of ethyl (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 0.22 g, 0.65 mmol) in 2M ammonia in methanol (5-6 mL) was heated in a closed vial at 60° C. for approximately 1 hour. The resulting mixture was cooled to ambient temperature and concentrated under reduced pressure, and the crude product was recrystallized from methanol to give the title compound, MS (ESI+) for C14H16N3O4F m/z 310 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:16]1[CH2:21][CH:20]2[CH:18]([CH:19]2[CH:22]=O)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH2:9]([N:16]1[CH2:21][CH:20]2[CH:18]([CH:19]2[CH:22]=[N:2][OH:3])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=CC1C2CN(Cc3ccccc3)CC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=CC1C2CN(Cc3ccccc3)CC12
Reaction time: 16 h
Yield: 91.2 %

Procedure:
Hydroxylamine hydrochloride (1.69 g, 22.84 mmol) and sodium acetate (2.45 g, 29.85 mmol) were added to a stirred solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (1.60 g, 7.96 mmol) in EtOH (100 ml) at r.t. under N2. The reaction was allowed to stir for 16 h. The solvent was then removed in vacuo and the residue partitioned between DCM (100 ml) and aq. K2CO3 (100 ml). The organic layer was separated and the aqueous layer washed with DCM (100 ml). The combined organic layers were dried (MgSO4) and solvent removed in vacuo to give the title compound as a yellow oil (1.57 g, 91%-1:1 mixture of oxime isomers). LCMS purity 85%, m/z 217 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.65 (4H, m), 1.86 (1H, m), 2.29 (4H, d, J=9 Hz), 2.50 (1H, m), 2.91 (4H, dd, J=2.4, 9 Hz), 3.57 (4H, s), 6.05 (1H, d, J=9 Hz), 6.96 (1H, d, J=8.1 Hz), 7.21-7.34 (10H, m), 10.28 (1H, s), 10.59 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:29][CH2:28]4)=[C:23]([NH2:26])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:38]#[N:39])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.C(N(CC)C1C=CC=CC=1)C.[C:51](Cl)(=[O:53])[CH3:52]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][CH:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:31][CH2:32]4)=[C:23]([NH:26][C:51](=[O:53])[CH3:52])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:38]#[N:39])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Yield: 87.8 %

Procedure:
By the procedure of Example 27, 0.1 g (0.18 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-amino-7-(4-pyrrolidin-1-yl piperidin-1-yl)quinoline-3-carbonitrile is reacted with 0.3 ml (1.9 mmol) of N,N-diethyl aniline and 0.04 ml (0.56 mmol) of acetyl chloride in 1.5 mL of NMP. The crude residue is purified by silica gel chromatography (gradient 95:5 methylene chloride/methanol to 4:1 methylene chloride/methanol) to give 95 mg of N-[4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-3-cyano-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinolin-6-yl]acetamide as a beige solid, mp 243-255° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10]C)=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17]>C(#N)C.O>[CH3:9][C:7]1[C:6](=[O:10])[CH:5]=[C:4]([CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:3](=[O:2])[CH:8]=1
Reactant: COc1cc(CCCOC(C)=O)c(OC)cc1C
Solvent: O
Solvent: CC#N
Product: CC(=O)OCCCC1=CC(=O)C(C)=CC1=O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 5 (1.26 g, 4.99 mmol) in acetonitrile (15 cm3) was added ceric ammonium nitrate (5.50 g, 9.99 mmol) in water (10 cm3) dropwise. The mixture was stirred for 1 hr before the organics were extracted with dichloromethane (3×25 cm3), washed with brine (25 cm3), dried (MgSO4) and concentrated under vacuum to yield the title compound as a brown oil 6 (756 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:16][CH:15]([O:17][Si](C(C)(C)C)(C)C)[CH2:14][CH:13]2[CH2:12][O:11][N:10]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH:5]=[CH:6][C:7]=1[F:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:16][CH:15]([OH:17])[CH2:14][CH:13]2[CH2:12][O:11][N:10]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN2OCC3CC(O[Si](C)(C)C(C)(C)C)CC32c2ccc(F)c(Br)c2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2OCC3CC(O)CC32c2ccc(F)c(Br)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6a-(3-bromo-4-fluorophenyl)-5-(tert-butyldimethylsilyloxy)-1-(2,4-dimethoxybenzyl)hexahydro-1H-cyclopenta[c]isoxazole (3.00 g, 4.77 mmol) in THF (10 mL) is added 1 N tetrabutylammonium fluoride solution in THF (7.15 mL, 7.15 mmol). After stirring at room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure to afford a residue that is diluted with dichloromethane and washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give a residue that is purified by silica gel chromatography eluting with a linear gradient of 0% to 10% methanol in dichloromethane over 20 minutes to give the title compound as a diastereomeric mixture (2.26 g, 100%). This mixture is purified again on silica gel chromatography to separate the diastereomers eluting with a linear gradient of 0% to 15% ethyl acetate in hexanes over 15 minutes to give the title compound as a racemic mixture (0.852 g, 37%). ES/MS m/e (79Br/81Br) 452, 454 (M+1).
Reaction SMILES: C[N:2]([CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4].NCCOCCOCCOCCC(OC(C)(C)C)=O>>[CH3:55][N:12]([CH2:11][CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3](=[O:4])[NH:2][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:68])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1
Reactant: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CC(C)(C)OC(=O)CCOCCOCCOCCN
Product: CN(CCN1CCC[C@H]1C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of tert-butyl 2-methyl-1-((S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidin-2-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 190, using tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate in place of tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate. MS (ES, m/z): 988.34 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1cc2c(s1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1cc2c(s1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C
Yield: 40 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:9]([N:11]1[CH2:28][CH2:27][CH2:26][C:13]2([C:17](=[O:18])[N:16]([CH3:19])[CH2:15][CH:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)[C:9]([N:11]1[CH2:28][CH2:27][CH2:26][C:13]2([C:17](=[O:18])[N:16]([CH3:19])[CH2:15][CH:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12]1)=[O:10]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccc(F)cc3)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [(R)-1-(4-Fluoro-benzyloxymethyl)-2-(2-methyl-1-oxo-4-phenyl-2,7-diaza-spiro[4.5]dec-7-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (diastereomer 2 from step 1) (185 mg, 0.34 mmol) in DCM (4 ml) was treated with TFA (0.79 ml, 10.3 mmol). The resulting solution was stirred for 2 h at RT. The reaction mixture was diluted with DCM (20 ml) and quenched at 0° C. with 2M NaOH aqueous solution (10 ml). The organic phase was separated, washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F>C(O)(=O)C>[CH:23]1[CH:24]=[CH:25][C:20]([C:12]([S:5][CH2:4][CH2:3][NH2:2])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:21][CH:22]=1.[ClH:1]
Reactant: NCCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: FB(F)F
Solvent: CC(=O)O
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1 equivalent of cysteamine hydrochloride and 1 equivalent of triphenylmethanol are dissolved in glacial acetic acid at 60° and treated with stirring with 1.1 equivalents of BF3 etherate. The mixture is stirred for one hour and worked up in the customary manner and Trt-cysteamine hydrochloride (“C”) is obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].CO.[C:17](C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:12]([O:13][CH3:17])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C)c2[nH]ccc12
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)cc(C)c2[nH]ccc12
Temperature: 110 °C

Procedure:
4-Allyl-7-methyl-1H-indol-5-ol (Example 1-C) (2.77 g, 14.79 mmol) was dissolved in toluene (74.0 mL) and methanol (0.599 mL, 14.79 mmol) was added followed by cyanomethylenetributylphosphorane (8.93 g, 37.0 mmol). The reaction was heated at 110° C. for 1 hour. The reaction was cooled to room temperature and then concentrated. The residue was then absorbed onto silica and purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 202.17 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li]CCCC.CCCCCC.[CH3:22][O:23][C:24]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:25]=1[CH2:26][NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=O)[O:32][CH2:31]2.Cl>C(COC)OC.CO>[CH3:22][O:23][C:24]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:25]=1[CH2:26][NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:32][CH2:31]2
Reactant: COc1ccc(CNc2ccc3c(c2)COC3=O)c(OC)c1
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: COCCOC
Solvent: CCCCCC
Product: COc1ccc(CNc2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
To a stirred solution of oxindole (555 mg, 4.17 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 2.5M n-BuLi solution in hexane (3.67 ml, 9.17 mmol), and the resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of 5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-one (1.0 g, 3.34 mmol). After stirred at room temperature for 2.5 hours the mixture was poured into 1M HCl aqueous solution (100 ml). The resulting solid was separated, washed with water, and dried under vacuum to afford a crude product. Trituration of the crude product with MeOH produced 3-[5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (630 mg, 46%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH3:21])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH:19]([CH3:21])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 27.6 %

Procedure:
6.0 g of 1-(2-chloroethyl)-3-isopropyl-3-D-galactopyranosylurea are dissolved in 20 ml of formic acid, and 4.2 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-isopropyl-3-D-galactopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)(O)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>ClCCl.CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH2:9][O:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH:12]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=CC(O)(c1ccccc1)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Phorphorus pentachloride (3.0 g, 14.2 mmoles) was suspended in dichloromethane (4 ml). To the suspension was added dropwise a solution of 1-phenyl-1-(3-pyridyl)-2-propen-1-ol (2.0 g, 9.5 mmoles) in dichloromethane (20 ml) at 0° C., then the mixture was stirred for one hour at room temperature, followed by washing with water, saturated aqueous solution of sodium hydrogen carbonate in the order. The organic layer is dried (magnesium sulfate), and concentrated to about 20 ml at a temperature not exceeding 30° C. The solution was further dried with molecular sieves 4A. This solution was named as (a) solution. Separately, sodium hydride (400 mg, 10 mmoles) is suspended in dimethylformamide (5 ml). To the suspension was added dropwise methyl metahydroxybenzoate (1.37 g, 9.0 mmoles) dissolved in dimethylformamide (5 ml). The mixture was stirred for 30 minutes at 0° C., to which was added dropwise the (a) solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured in ice-water, which is subjected to extraction with ethyl acetate, washed with water and dried (magnesium sulfate), followed by removing the solvent by evaporation under reduced pressure. The residue was subjected to silica-gel column chromatography, using ether-ethyl acetate (7:3) as eluant to yield methyl 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoate (If-56) (3.0 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[CH:30]([CH2:38][CH3:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH:30]([CH2:38][CH3:39])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:24]C(=O)OC(C)(C)C)[CH:12]([OH:23])[C:13](=[O:22])[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:5])=[O:4].[ClH:33]>C(OCC)(=O)C>[ClH:33].[ClH:33].[NH2:24][C@@H:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:3]([N:2]([CH3:32])[CH3:1])(=[O:5])=[O:4])[CH:12]([OH:23])[C:13]([NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:22]
Reactant: CN(C)S(=O)(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)NCc1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)NCCCC[C@H](N)C(O)C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A 0° C. solution of 1.13 g (2.4 mmol) of tert-butyl (1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{1-hydroxy-2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}pentylcarbamate in 100 mL of ethyl acetate was bubbled with hydrogen chloride gas for 5 min and stirred at room temperature for 30 min before being concentrated under reduced pressure to afford 1.06 g (>99%) of (3S)-3-amino-7-{[(dimethylamino)sulfonyl]amino}-2-hydroxy-N-(3-pyridinylmethyl)heptanamide dihydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 8.92 (t, J=6 Hz, 1H), 8.76 (m, 2H), 8.09 (bs, 1H), 7.87 (m, 2H), 7.17 (m, 1H), 6.68 (m, 1H), 4.46 (m, 2H), (4.32 (d, J=3 Hz) and 4.18 (d, J=3 Hz), 1H), 3.37 (m, 1H), 2.83 (m, 2H), 2.67 (s, 6H), 1.25-1.60 (m, 6H). ES-LCMS m/z 374 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27]CC1C=CC=CC=1)[OH:20])C1C=CC=CC=1>C(OCC)(=O)C.C(O)C>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19]([OH:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27]
Reactant: O=c1ccn(CCO)c(C(O)c2ccccc2OCc2ccccc2)c1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1ccn(CCO)c(C(O)c2ccccc2O)c1O

Procedure:
3-Benzyloxy-2-[(2-benzyloxy-phenyl)-hydroxy-methyl]-1-(2-hydroxy-ethyl)-.1H-pyridin-4-one: From 2.42 g of 3-benzyloxy-2-[(2-benzyloxy-phenyl)-(tetrahydropyran-2-yloxy)-methyl]-1-(2.-hydroxy-ethyl)-1H-pyridin-4-one there is obtained analogously to Example 6e, after chromatography: 3-benzyloxy-2-[(2-benzyloxy-phenyl)-hydroxy-methyl]-1-(2-hydroxy-ethyl)-1H-pyridin-4-one. Beige foam. Rf value: 0.17 (silica gel 60, ethyl acetate/ethanol 9/1).