Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][N:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1c[nH]c2c1-c1ncccc1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1c[nH]c2c1-c1ncccc1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
A mixture of 130 mg (0.53 mmol) of 3,4,5,6-Tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid methyl ester and 0.6 mL (0.6 mmol of benzaldehyde is dissolved in 10 mL of dichloroethane. To this solution is added 270 mg (1.3 mmol) of sodium triacetoxyborohydride and the resulting mixture is stirred for 18 hours at room temperature. A 10 mL solution of saturated Na2HCO3 is added, and the reaction stirred for 60 minutes. The organic layer is separated from the aqueous layer, dried (Na2SO4) and evaporated. The residue is chromatographed on 10 grams of silica gel using 50/1 chloroform/methanol as the eluant. Appropriate fractions are combined to yield 118 mg of 5-benzyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo[e]azulene-1-carboxylic acid methyl ester. 1H NMR (CDCl3) δ10.1 (s, 1H), 8.6 (d, 1H), 7.55 (d, 1H), 7.3 (m, 6H), 7.1 (m, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 3.55 (s, 2H), 3.35 (s, 2H). Mass spectrum: m/e 334.3 (p +1). TLC (10/1 chloroform/methanol) Rf=0.15.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:49]1([C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])=[O:56])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C=O)C.O>[O:25]=[C:23]([N:52]1[CH2:53][CH2:54][N:49]([C:55](=[O:56])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:64])[F:65])[CH2:50][CH2:51]1)[CH2:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[CH:12]2)=[O:20]
Reactant: O=C(O)CNC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
DIPEA (0.111 mL, 0.64 mmol) was added to a stirred solution of [(1H-Indole-5-carbonyl)-amino]-acetic acid (40 mg, 0.18 mmol) in DMF (1.0 mL). HOBT (29 mg, 0.22 mmol) and EDCI.HCl (42 mg, 0.22 mmol) were added, followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (59 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the resulting precipitate was filtered to afford 1H-Indole-5-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}-amide in 45% yield. LC-MS purity: 91%, 1H NMR (CDCl3): δ 8.48 (s, 1H), 8.18 (s, 1H), 7.78-7.54 (m, 4H), 7.42-7.30 (m, 2H), 7.28 (s, 1H), 6.62 (s, 1H), 4.40-4.20 (m, 2H), 4.18-3.82 (m, 2H), 3.78-3.52 (m, 4H), 3.24 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].C(N(C(C)C)C(C)C)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][S:29]([CH3:32])(=[O:31])=[O:30])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@@H](O)[C@@H](NC(=O)c2ccc(Cl)s2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C

Procedure:
A solution of (1R,3S,4R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentane-carboxylic acid methyl ester (136 mg) in CH2Cl2 (5 ml) was treated at 0° C. with N-ethyl-diisopropyl amine (0.38 ml) and mesyl chloride (0.04 ml). The reaction mixture was stirred at 0° C., then diluted with H2O and extracted with CH2Cl2. The organic layer was washed with H2O, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2MeOH 95:5) to give (1R,3S,4R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methanesulfonyloxy-cyclopentanecarboxylic acid methyl ester (159 mg) as off-white solid. MS 380.1 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H](C)CCCS(NC)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.O=S1(=O)CCC(N)C1>>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCCS(=O)(=O)Cl
Agent: NC1CCS(=O)(=O)C1
Product: NS(=O)(=O)c1ccccc1
Yield: 23 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[[(tetrahydro-], 1-dioxido-3-thienyl)amino]sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with tetrahydro-1,1-dioxido-3-thienylamine. Yield=23%; MS (ESI+), 603 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCN([C:22]2[CH:23]=CC([N+]([O-])=O)=C(N)[CH:27]=2)CC1)C.CC(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O.C(O)(=O)C.C(Cl)Cl>[CH:22]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)([CH3:23])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Boc piperizine, 1 (10 g, 53.76 mmol) and acetone (4 mL) was taken in a mixture of dry DCM (100 mL) and acetic acid (3.2 mL). Stirred at room temperature for 20 min. Added Na(OAc)3BH (17 g, 80.2 mmol) and stirring continued at room temperature for 12 hr. The reaction mixture was diluted with water, extracted with ethyl acetate (3×25 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to get crude title compound (13 g, crude). MS (ESI): 229.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:9]1=[O:24].[N+:25]([O-])([O-:27])=[O:26].[K+]>S(=O)(=O)(O)O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:25]([O-:27])=[O:26])=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C:9]1=[O:24]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1nc(-c2ccccc2)c2ccccc2n1Cc1ccccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.13 g of 1-(2-pyridylmethyl)-4-phenyl-2(1H)-quinazolinone in 10 ml of concentrated sulfuric acid was added dropwise a solution of 1 g of potassium nitrate in 3 ml of concentrated sulfuric acid with cooling by an ice bath. The resulting mixture was stirred at room temperature for 3 hours and then poured onto cracked ice. The precipitate was collected by filtration, washed successively with water and ammonia water and dried to give 1-(2-pyridylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone. Recrystallization from chloroform gave colorless fine crystals, m.p. 175°-176° C.
Reaction SMILES: [C:1]([CH:4]1[CH:18]2[CH:7]([CH2:8][C:9]3[C:17]4[C:16]2=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=3)[N:6]([CH3:28])[CH2:5]1)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:35][OH:36]>CO>[C:22]1([S:19]([N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[CH:18]5[CH:7]([C:8](=[N:35][OH:36])[C:9]([C:17]=34)=[CH:10]2)[N:6]([CH3:28])[CH2:5][CH:4]5[CH3:1])(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NO
Reactant: CC(=O)C1CN(C)C2Cc3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1CN(C)C2C(=NO)c3cn(S(=O)(=O)c4ccccc4)c4cccc(c34)C12

Procedure:
To a stirred solution of the 9-acetyl compound of Example 4 (0.25 g) in methanol (12 cm3) was added anhydrous sodium acetate (0.078 g) and hydroxylamine hydrochloride (0.0615 g) and the orange solution heated to reflux. After 5 hours reaction was indicated to be complete, all solvents were removed under vacuum. Chloroform (40 cm3) and water (40 cm3) was added and the residue partitioned. The organic layer was re-washed with water (25 cm3), dried and evaporated under vacuum to give a yellow-white solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([O:16][C@H:17]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>C1(C)C=CC=CC=1.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>[CH:33]([C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([O:16][C@H:17]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1)=[CH2:34]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)c(O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)nc1ccccc12

Procedure:
To a degassed solution of the product mixture from Step 3 (320 mg, 0.64 mmol) in PhMe (5 mL) was added vinyltributyltin (0.225 mL, 0.77 mmol) and tetrakis(triphenylphosphine)palladium (74 mg, 0.06 mmol). The mixture was then heated to reflux for 18 h. The solvent was then removed in vacuo and the crude material was purified on silica (gradient elution, 5-50% EtOAc/hex) to provide the title compound as a 1:1 mixture with the expected regioisomer. LRMS ((M-Boc)+H)+=349.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C1C(=O)N([I:17])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:17])=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 25 °C

Procedure:
10.0 g (70 mmol) 4-Chloro-6-methyl-pyrimidin-2-ylamine in 200 mL acetic acid is cooled to 0° C., 15.7 g (70 mmol) NIS is added and the reaction mixture is stirred at RT until conversion of the starting material is completed (18 h). An aqueous solution of 5% Na2S2O3 and 10% NaHCO3 is added until the mixture decolorizes. The formed precipitate is filtered off, taken up with water and the resulting suspension is stirred at RT for 1 h. The product is filtered off and dried in vacuo at 40° C. Yield: 15.2 g (81%). 1H NMR (CDCl3) δ: 5.2 (s, 2H), 2.6 (s, 3H). TLC (silica, 20% EtOAc in PE): Rf=0.50.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 39.8 %

Procedure:
4Hydroxybenzaldehyde (24.4 g, Aldrich) was dissolved in absolute ethanol (470 ml) and anhy. K2CO3 (27.6 g) and ethyl 2-bromoisobutyrate (39.0 g, Aldrich) added. The resulting mixture was refluxed overnight, allowed to cool and the solvent removed in vacuo. The residue was suspended in water (300 ml) and extracted with CH2Cl2. The combined organic layers were washed with 1.0N aqu. NaOH and water, then dried over MgSO4. Removal of the solvent in vacuo and vacuum distillation of the residue gave the desired product (18.8 g, bp 110°-118° C./0.1 mm Hg).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@H:10]([C:21]([N:45]2[CH2:46][CH2:47][N:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=3)[CH2:43][CH2:44]2)=[O:22])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2ccc(Cl)cc2)C1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)N(Cc2ccc(Cl)cc2)C1
Yield: 10 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(4-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 1-(3-trifluoromethyl-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (70.8 mg) in 10% yield as colorless oil. MS m/e=708.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>C(O)(=O)C.O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[C:13]([I:15])[C:8]=3[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: Oc1ccc2c(c1)nnn2CC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(nnn2CC2CC2)c1I
Reaction time: 0.25 h

Procedure:
1-(Cyclopropylmethyl)-1H-benzotriazol-5-ol (5.41 g, 28.6 mmol) was dissolved in acetic acid (75 mL) and treated with N-iodosuccinimide (4.79 g, 21.3 mmol, 0.74 equiv) portionwise. After 15 minutes, the mixture was diluted with water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>O1CCCC1>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: c1ccc(Nc2nc3ccccc3s2)cc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCCN(c1ccccc1)c1nc2ccccc2s1
Reaction time: 0.25 h
Yield: 66 %

Procedure:
Sodium hydride (0.05 mol) was added portionwise to a solution of N-phenyl-2-benzothiazolamine, prepared according to the procedure described in J. Chem. Soc, 1962, 230, (0.05 mol) in tetrahydrofuran (200 ml). The mixture was stirred for 15 minutes. A solution of 1-bromo-4-chlorobutane (0.05 mol) in tetrahydrofuran (50 ml) was added dropwise and the resulting reaction mixture was stirred and refluxed for 48 hours. The mixture was cooled, and the solvent was evaporated. The residue was partitioned between water and CH2Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated, yielding 10.4 g (66%) of N-(4-chlorobutyl)-N-phenyl-2-benzothiazolamine (interm. 10). N-(5-chloropentyl)-N-phenyl-2-benzothiazolamine (interm. 24) was prepared similarly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][CH2:20]Cl)=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-:23].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][CH2:20][I:23])=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1C(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C(c1ccccc1)C1CCCCN1C(=O)OCI
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of 37 (0.28 g, 0.86 mmol) and sodium iodide (0.387 g, 2.58 mmol) in acetone (6 mL) was stirred overnight. The acetone was evaporated. The residue was dissolved in ethyl acetate (80 mL) and washed with saturated sodium bisulfate (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried in vacuum to give 38 as a syrup (0.263 g) (yield, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:29]1[C@H:38]2[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:29]3[C@H:38]4[C@@H:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)[CH2:32][CH2:31][CH2:30]3)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC[C@H]2NCCC[C@@H]2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), trans-decahydroquinoline (1:1 mixture of the trans-isomers; 0.35 mmol) and HATU (0.35 mmol) were added and the reaction stirred at room temperature for 5 hours. The solvent was evaporated and the residue was purified by HPLC, eluting with 10%-90% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.09 g). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.5-3.3 (m, 2H), 3.0-2.7 (m, 3H), 2.25 (m, 1H), 2.0 (m, 2H), 1.8-1.5 (m, 8H) 1.5 (s, 9H), 1.4-1.0 (m, 6H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([CH3:11])=[CH2:10]>>[CH2:10]([CH:3]1[C:4](=[O:5])[O:6][C:1](=[O:7])[CH2:2]1)[C:9](=[CH2:8])[CH3:11]
Reactant: C=C(C)C
Reactant: O=C1C=CC(=O)O1
Product: C=C(C)CC1CC(=O)OC1=O

Procedure:
reacting maleic anhydride with 2-methylpropene to yield β-methallylsuccinic anhydride;
Reaction SMILES: O.NN.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH2:26][N:27]2C(=O)C3C(=CC=CC=3)C2=O)([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO>[NH2:27][CH2:26][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:16][CH2:15]1)([C:18]([O:20][CH3:21])=[O:19])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)C(CN)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of 2.9 ml (64 mmol) of hydrazine hydrate in 8 ml of methanol is added to a solution of 27.5 g (58 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonate in 300 ml of methanol cooled beforehand to −5° C. The reaction medium is stirred at from −5° C. to ambient temperature over the course of 3 h. After evaporation and addition of 300 ml of water, the reaction medium is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with an 8/2 heptane/ethyl acetate mixture and then an increase in polarity up to a 90/10 ethyl acetate/methanol mixture. 10 g (50%) of dimethyl 2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are thus obtained in the form of a light oil.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.CO.[CH3:16][Si](C=[N+]=[N-])(C)C.CCCCCC>C1COCC1>[NH2:1][C:2]1([C:5]2[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:16])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC1(c2ccc(C(=O)O)cc2)CC1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc(C2(N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
4-(1-aminocyclopropyl)benzoic acid (1.75 g, 0.00988 mol) was stirred in THF (20 mL) and Methanol (10 mL) over ice/water bath. 2.00 M of trimethylsilyldiazomethane in hexane (9.9 mL, 0.020 mol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated down to viscous oil which solidified upon standing to give a crystalline solid. Crude material was dried on high vacuum line for 12 hours to give methyl 4-(1-aminocyclopropyl)benzoate (1.65 g, 87%) as pale brown solid. Step 2:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:17])[CH3:16])[N:11]=[CH:10]1>CC(O)=O.C1COCC1>[Br:1][C:13]1[S:9][CH:10]=[N:11][C:12]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1cscn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Nc1ncsc1Br
Temperature: 25 °C
Yield: 54.3 %

Procedure:
1-Bromopyrrolidine-2,5-dione (0.48 g, 2.67 mmol) was added to the solution of N-(thiazol-4-yl)acetamide (0.38 g, 2.67 mmol) in AcOH/THF (10 mL/10 mL). The mixture was heated to 25° C. for 2 h. The solvent was removed and the solution was adjusted to pH˜9 with 2 N NaOH solution. It was extracted with EA (3×50 mL), the combined organic phase was washed with brine, dried with Na2SO4 and concentrated to give the title compound (1.32 g, 1.45 mmol, 54.2%) as light yellow solid.
Reaction SMILES: S(O)(O)(=O)=O.[F:6][CH2:7][CH2:8][N:9]1[C:13]([NH2:14])=[C:12]([NH2:15])[CH:11]=[N:10]1.O=C1CCC(=O)N1[O:23][C:24](=O)[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])O.[Na+].[Cl-].[Na+]>O1CCCC1>[NH2:14][C:13]1[N:9]([CH2:8][CH2:7][F:6])[N:10]=[CH:11][C:12]=1[NH:15][C:24](=[O:23])[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn(CCF)c1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn(CCF)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a suspension of 1-(2-fluoroethyl)-1H-pyrazole-4,5-diamine sulfate (3 g) in tetrahydrofuran (30 ml) were added tert-butyl {3-[(2,5-dioxo-1-pyrrolidinyl)oxy]-3-oxopropyl}carbamate (3.9 g) and N,N-diisoporpylethylamine (3.5 g) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. An aqueous sodium hydrogen carbonate solution and sodium chloride were added, and the mixture was extracted with ethyl acetate-tetrahydrofuran (three times). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate→ethyl acetate:ethanol=8:1) to give tert-butyl (3-{[5-amino-1-(2-fluoroethyl)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (2.3 g).