Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.CN1C(=O)CCC1>O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCC(C)(N)C(=O)OC
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(C)(Nc1ccnc(Cl)n1)C(=O)OC
Temperature: 80 °C
Yield: 98.1 %

Procedure:
A 250 mL flask was charged with methyl 2-amino-2-methylbutanoate (8.4 g, 54.4 mmol), 2,4-dichloropyrimidine (8.9 g, 59.8 mmol), TEA (5.5 g, 54.4 mmol) and 80 mL NMP. The reaction mixture was heated to 80° C. for ˜18 hours. After cooling, water (300 mL) was added and the mixture extracted with MTBE. The organic extracts were washed with water and dried over sodium sulfate. Filtration and evaporation under vacuum afforded 13 g of an orange oil which was purified by flash chromatography, (0-100% ethyl acetate-hexane affording 4.6 g (34%) methyl 2-((2-chloropyrimidin-4-yl)amino)-2-methylbutanoate as an oil. 1H NMR: (CDCl3) δ 8.05-7.88 (m, 1H), 6.28 (δ, 1H), 5.95 (δ, 1H), 4.2-4.0 (μ, 1H), 3.86 (m, 1H), 2.46 (m, 1H), 2.10 (m, 1H), 2.01 (m, 1H), 1.72 (m, 3H), 0.89 (m, 3H). m/e, m+1 244.1
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([Br:14])[C:3]=1[C:4]#[N:5].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1)#[CH:16].CCN(C(C)C)C(C)C>>[Br:14][C:6]1[C:3]([C:4]#[N:5])=[C:2]([C:16]#[C:15][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:21][CH:22]=2)[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)c(C#N)c(Br)c1
Reactant: C#Cc1ccc(NS(C)(=O)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(Br)c(C#N)c(C#Cc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 80 °C
Yield: 35.8 %

Procedure:
step 2—A mixture of 92 (0.750 g, 1.90 mmol), Cu(I) (0.027 g, 0.09 mmol), Pd(II)(PPh3)2Cl2 (0.203 g, 0.19 mmol), 80 (0.748 g, 2.85 mmol) and DIPEA (5 mL mL) under an argon atmosphere was heated overnight at 80° C. The reaction was cooled to RT then concentrated. The crude residue was purified by SiO2 chromatography eluting with 40% EtOAc/hexanes to afford 0.293 g (24%) of N-[4-(3-bromo-5-tert-butyl-2-cyano-phenylethynyl)-phenyl]-methanesulfonamide (94) as a light brown solid.
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][N:4]1C(=O)CCC1=O.[ClH:19]>C(O)C.O>[ClH:19].[NH2:4][CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1CC(O)COc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NCC(O)COc1ccccc1

Procedure:
A solution of 1-(2-hydroxy-3-phenoxypropyl)pyrrolidine-2,5-dione (3.5 g, 13.1 mmol) (as shown at 3 above) in HCl (12N, 20 mL) and ethanol (20 mL) was heated to reflux for 6 hours. After thin layer chromatography (TLC) showed the reaction was complete, the mixture was concentrated in vacuum to give a white residue, which was taken up in water (20 mL) and washed with ether (3*50 mL). The aqueous phase was concentrated to give crude product, which was crystallized from methanol to give 2.9 g of 1-amino-3-phenoxypropan-2-ol hydrochloride (as shown at 4).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4].[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH:53]([C:47]1[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[N:39]1[C:38](=[O:56])[CH2:37][S:41]/[C:40]/1=[N:42]\[C:43]([NH:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:5])=[O:44])([CH3:55])[CH3:54]
Reactant: CC(C)(CN)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCC(C)(C)c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CB29) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown glassy foam (0.084 g, 46%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]1[N:19]([CH3:31])[C:20](=[O:30])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:22][C:12]2=1)=O)[CH3:2].O.[NH2:35][NH2:36]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:31])[C:20](=[O:30])[C:21]([C:23]4[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=4)=[CH:22][C:12]3=2)[NH:36][N:35]=1)=[O:33])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)[nH]n1

Procedure:
The process is carried out as in Example 43 above, with compound A, 4-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2,4-dioxobutyric acid ethyl ester and hydrazine monohydrate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][CH2:11][Cl:12].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21]
Reactant: ClCCCSc1ccccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=S(CCCCl)c1ccccc1Br

Procedure:
Prepared by Procedure S and Scheme AA using 1-bromo-2-[(3-chloropropyl)sulfanyl]benzene and 1 eq m-CPBA: ESMS m/e: 282.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH:18]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[C:17](=[O:24])[C:12]3[CH:11]=[CH:16][CH:15]=[CH:14][C:13]=3[O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(Cn1cncn1)c1ccccc1O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2OC(c2ccc(Cl)cc2)C1n1cncn1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Chlorobenzaldehyde (1.18 g) was added to 2'-hydroxy-2-(1,2,4-triazol-1-yl)acetophenone, obtained in Example 6 (1.7 g), in dry dimethylformamide (20 ml). The mixture was stirred at 90° C. for 24 hours. It was then poured into ice/water, extracted with dichloromethane and the extract dried and evaporated. The residual oil was triturated with diisopropyl ether to give 2-(4-chlorophenyl)-2,3-dihydro-3-(1,2,4-triazol-1-yl)-benzopyran-4-one, m.p. 140°-1° C. (Compound 15).
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH:16]([CH3:18])[CH3:17])[O:10]C1(C)C)=O)(C)(C)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH2:32])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[NH2:8][C@H:12]([C:13]1[NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:26][C:27]=2[N:32]=1)[C@H:11]([OH:10])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)[C@@H](O)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4S,5R)-3-(tert-butoxycarbonyl)-5-isopropyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 60) and 4-tert-butyl-1,2-diaminobenzene. The final residue was washed with ethyl acetate and diluted with water, basified with saturated lithium hydroxide solution (pH=8), extracted with ethyl acetate and dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:27]([O:28]C(=O)C)[C@H:26]([O:32]C(=O)C)[C@@H:25]([CH2:36][O:37]C(=O)C)[O:24][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO.O1CCCC1>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=1)[C@@H:6]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:32])[C@H:27]([OH:28])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(N(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of 2-[4-(N,N-dimethylamino)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (00.10 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was added sodium methoxide (28% methanol solution, 0.007 mL), and the mixture was stirred at room temperature for 70 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: dichloromethane/methanol=8/1) to give 2-[4-(N,N-dimethylamino)benzyl]phenyl β-D-glucopyranoside (0.069 g).
Reaction SMILES: [CH2:1]([N:4]([CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[C:5](=[O:43])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3([C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:28]4[C:23]3=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:14][CH2:13]2)=[N:8][CH:7]=1)[CH:2]=[CH2:3]>CO.C(Cl)Cl.[Pd]>[CH:44]1([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:43])[C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]4([C:35](=[O:42])[NH:36][CH2:37][C:38]([F:41])([F:39])[F:40])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[C:29]5[C:34]4=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:14][CH2:13]3)=[N:8][CH:7]=2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: C=CCN(C(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc1)C1CCCCC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCCN(C(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc1)C1CCCCC1
Reaction time: 4 h
Yield: 84.6 %

Procedure:
The compound (50 mg, 0.07 mmol) prepared in Example 113 was dissolved in 1 ml of methanol and 0.5 ml of methylene chloride. 10% Pd—C (5 mg) was added to the solution. The mixture was subjected to catalytic reduction under the atmospheric pressure at room temperature for 4 hr. The reaction solution was filtered, and the solution was concentrated under the reduced pressure to give the title compound (40 mg, yield 80%) as a white foam.
Reaction SMILES: O1CCCC1.P(Br)(Br)[Br:7].CC1C=CC(S(O[C:21]2[CH2:25][CH:24]([C:26](=[O:43])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[C:35](=[O:42])[NH:36][CH:37]([CH:39]3[CH2:41][CH2:40]3)[CH3:38])[N:23]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:22]=2)(=O)=O)=CC=1>O>[Br:7][C:21]1[CH2:25][CH:24]([C:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[C:35](=[O:42])[NH:36][CH:37]([CH:39]2[CH2:41][CH2:40]2)[CH3:38])=[O:43])[N:23]([C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[N:22]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 235.1 %

Procedure:
A tetrahydrofuran (1 ml) solution comprising 0.16 g of phosphorus tribromide was dropwise added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 9 ml of tetrahydrofuran under cooling with ice. After stirring for 5 minutes, the reaction liquid was heated to 45° C. 5 hours later, the reaction liquid was poured to 50 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.73 g of the desired product in the form of a paste.
Reaction SMILES: [CH2:1]([N:8]1[CH2:33][CH2:32][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([N:16]3[C@H:21]([CH3:22])[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:18]([CH3:30])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:33][CH2:32][C:11]2[N:12]=[C:13]([C:36]3[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:35]=3[CH3:34])[N:14]=[C:15]([N:16]3[C@H:21]([CH3:22])[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:18]([CH3:30])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1nc2c(c(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)n1)CN(Cc1ccccc1)CC2
Temperature: 140 °C

Procedure:
To a solution of racemic tert-butyl 4-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.54 g, 1.14 mmol) in DME (9 mL) was added 2,6-dimethylphenylboronic acid (0.257 g, 1.72 mmol), Pd(Ph3P)4 (0.198 g, 0.172 mmol) and a 2 M aq solution of sodium carbonate (1.9 mL). The reaction was heated at 140° C. in a microwave reactor for 1.75 h. The reaction was filtered and diluted with EtOAc and brine. The organic layer was separated and then dried (Na2SO4), filtered and concentrated. The residue was then purified by FCC (55-80% EtOAc/heptane) to give the title compound. MS (ESI+) m/z 542.5 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([O:12][CH3:17])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a solution of (4R)-1-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) prepared in Step A in DMF was added K2CO3 (14 g, 101 mmol) and methyliodide (2.6 ml, 51.9 mmol). The reaction mixture was stirred at rt for 5 h, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (8.0 g, 95%).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH:7]([NH:11][CH:12]1[CH2:14][CH2:13]1)[CH:8]([CH3:10])[CH3:9])C.II.[H][H]>C1COCC1.CO>[CH:12]1([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][OH:5])[CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: CCOC(=O)C(NC1CC1)C(C)C
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(CO)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (167 mg) was added to dry THF (10 mL) under argon and cooled to 0° C. To this mixture was added 2-cyclopropylamino-3-methyl-butyric acid ethyl ester (341 mg, obtained in example 25, step A]) followed by a solution of iodine (467 mg) in THF (5 mL) that was added over a period of 30 minutes. A strong hydrogen evolution was observed. The mixture was stirred at 0° C. for 30 minutes and then heated to reflux for 12 hours. The mixture was cooled and methanol was carefully added until a clear solution was obtained. After 30 minutes, the mixture was evaporated. The residue was treated with 20% aqueous KOH solution for 4 hours. The mixture was extracted with DCM three times and the combined organic layers were dried over Na2SO4 and evaporated to give crude 2-cyclopropylamino-3-methyl-butan-1-ol as a light yellow liquid (195 mg) that was used without further purification.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[Na+].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:2])=[O:22])=[CH:16][CH:15]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1ccc(CC=O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)O)cc1
Temperature: 20 °C
Reaction time: 17 h
Yield: 9896.6 %

Procedure:
1.44 equivalents (7.7 g) of sodium periodate NaIO4, 0.6 mol % (0.045 g) of sodium dichromate Na2Cr2O72H2O and 3 g of 1N sulfuric acid H2SO4 (12 mol %) were dissolved in 50 ml of water. To this solution were added 25 mmol (3.75 g) of 4-methoxyphenylacetaldehyde and 25 ml of toluene, whereupon the reaction mixture was stirred for 17 h at 20° C. The phases were then separated and the aqueous phase was extracted with 2×10 ml of toluene. 30 ml of 1N NaOH were added to the combined toluene phases. The basic water phase was made acidic with 3 g of conc. H2SO4 and extracted with 2×25 ml of toluene. The combined organic phases were washed 3× with H2O, dried over Na2SO4 and evaporated to dryness. 17 mmol (2.82 g) of p-methoxyphenylacetic acid (yield 68% of theory) with a purity of 98% were obtained.
Reaction SMILES: CC(N(C)C)=O.BrCCBr.[Si](Cl)(C)(C)C.[C:16]([N:23]1[CH2:26][CH:25](I)[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[Cl:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([Cl:36])[N:30]=1>[Zn]>[Cl:28][C:29]1[CH:34]=[C:33]([CH:25]2[CH2:26][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH:32]=[C:31]([Cl:36])[N:30]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
To a suspension of zinc (3.56 g, 3.0 equiv., 53.1 mmol) in DMA (8.3 mL, 88.5 mmol) was added 1,2-dibromoethane (0.37 mL, 0.24 equiv., 4.25 mmol), followed by TMS chloride (0.55 mL, 0.24 equiv., 4.25 mmol). After the reaction ceased down, a solution of 1-boc-3-(iodo)azetidine (11.3 g, 2.2 equiv., 39.0 mmol) in DMA (6.6 mL, 70.8 mmol) was added dropwise. After 30 min at 25° C. and then 2 h at 50° C., LCMS showed no m/z 228 peak. The mixture was transferred dropwise into a suspension of 2,6-dichloro-4-iodopyridine (5.00 g, 17.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride dichloromethane adduct (738 mg, 0.050 equiv., 0.885 mmol) and cuprous iodide (337 mg, 0.10 equiv., 1.77 mmol) in DMA (16.5 mL, 177 mmol). DMA (16.5 mL, 177 mmol)) was used to rinse the flask. The whole reaction mixture was kept at 80° C. in oil-bath for 4 h. DMA was removed at 60° C. under vacuum, and the crude was purified via silica gel chromatography (0-50% EtOAc/Heptanes) to yield 1.73 g (54% based on the conversion) of the title compound. 1H NMR (400 MHz, CDCl3) δ (delta) 7.23 (s, 2H), 4.35 (t, J=8.7 Hz, 2H), 3.92 (dd, J=8.7, 5.6 Hz, 2H), 3.73-3.61 (m, 1H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ (delta) 157.03, 156.08, 151.09, 121.24, 80.24, 55.31, 32.48, 28.32. LCMS: m/z 303 (M+H).
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6])C=C.[OH-].[Na+]>CO.O1CCCC1>[C:16]([O:15][C:13]([C:12]([CH3:21])([O:11][C:10]1[CH:9]=[C:8]([CH2:7][C:5]([OH:6])=[O:4])[CH:24]=[CH:23][CH:22]=1)[CH3:20])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[3-(allyloxycarbonylmethyl)phenoxy]-2-methylpropionate (3.35 g, 10.62 mmol) was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL). Subsequently, an aqueous 2M sodium hydroxide solution (40 mL) was added thereto, and the mixture was stirred for three hours at room temperature. The resultant mixture was concentrated under reduced pressure, and the resultant concentrate was acidified with 3M hydrochloric acid. The mixture was extracted with chloroform, followed by drying over sodium sulfate and concentration under reduced pressure, whereby the target compound was obtained (2.98 g, 10.12 mmol, 95.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]1[N:14]([CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH2:13][CH2:12][N:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:10]12>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:14]2[CH2:13][CH2:12][N:11]3[CH2:21][CH2:22][CH2:23][CH2:24][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Reactant: Nc1ccc(Cl)cc1
Product: O=C(CCCN1CCN2CCCCC2C1)Nc1ccc(Cl)cc1

Procedure:
The procedure is as for Example 2 using as substrate 4-chloroaniline and the compound obtained in Step B of Example 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].S(Cl)(Cl)(=O)=O.[C:30]([O:34][C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:36])[NH:37][C@H:38]([C:39](=[O:40])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:7][OH:8])[CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)c(N)c1
Yield: 38 %

Procedure:
The title compound was prepared from the crude amine mixture of (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-3-amino-4-fluoro-benzenesulfonamide which is described earlier (example 53, step C, which was made from a batch of sulfonyl chloride containing the two regioisomers) and (2S)-2-tert-butoxycarbonylamino-3-naphthalen-2-yl-propionic acid using general procedure A. The crude residue was purified by semi-preparative HPLC in several batches of 80 mg using a gradient of 35 to 90% of acetonitrile over 30 min and a flow rate of 15 mL/min, retention time=23.9 min. All the pure fractions were combined to provide 460 mg (38% yield) of the title compound.