Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6]([C:8]1([CH2:17][CH3:18])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](=[O:16])[CH2:9]1)[CH3:7].[NH4+].[Cl-]>CCOCC>[CH2:3]([C:10]1([OH:16])[CH2:11][C:12]([CH3:14])([CH3:15])[CH2:13][C:8]([CH2:6][CH3:7])([CH2:17][CH3:18])[CH2:9]1)[CH:2]=[CH2:1]
Reactant: CCC1(CC)CC(=O)CC(C)(C)C1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC1(O)CC(C)(C)CC(CC)(CC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a stirred 1 M etheral solution of allylmagnesium bromide (20 ml, 20 mmol) was added dropwise a solution of 3,3-diethyl-5,5-dimethylcyclohexanone (25) (1.47 g, 8.06 mmol) in dry ether (5 ml). The mixture was stirred for 1 h at ambient temperature and boiled at reflux for 10 min. Then it was cooled with ice water and treated with saturated aqueous NH4Cl (40 ml). The organic layer was separated and washed with water and brine. After drying over anhydrous MgSO4, the solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel (light petroleum ether). A fraction with Rf 0.7 (Hexane:EtOAc, 13:2) was collected. Evaporation of the solvent afforded 26 (1.35 g, 74%) as a colorless oil. 1H NMR (CDCl3, TMS): 0.74 (6H, t, 7 Hz, 2CH3 of ethyl); 0.88 (3H, s, 5-CH3eq); 1.19 (3H, s, 5-CH3ax); 0.80-2.05 (10H, m, 2,4,6-CH2 and 2CH2 of ethyl); 2.14 (2H, d, 7 Hz, CH2C═); 4.95-5.30 (2H, m, ═CH2) and 5.65-6.20 ppm (1H, m, ═CH).
Reaction SMILES: C(N(C(C)C)C(C)C)C.CC(C)=CCBr.NCC1N=C([C:23]2[N:24]=[CH:25][N:26]3[C:32]4[CH:33]=[CH:34][S:35][C:31]=4[C:30](=[O:36])[N:29]4[CH2:37][CH2:38][C@H:28]4[C:27]=23)ON=1>C(Cl)Cl>[CH:23]1[N:24]=[CH:25][N:26]2[C:32]3[CH:33]=[CH:34][S:35][C:31]=3[C:30](=[O:36])[N:29]3[CH2:37][CH2:38][CH:28]3[C:27]=12
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)n1
Agent: CC(C)=CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2sccc2-n2cncc2C2CCN12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.5 ml (8.6 mmol) of N-ethyldiisopropylamine and 0.28 ml (2.4 mmol) of dimethylallyl bromide were added to a solution of 453 mg (1.2 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of methylene chloride and the mixture was stirred at room temperature for 20 hours. The reaction solution was subsequently diluted with methylene chloride and washed three times with water. The organic phases were dried with magnesium sulfate, filtered and evaporated. The is residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). There were obtained 240 mg (43%) of (S)-1-[3-bis-[3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-5-yl]-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.55 (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1).
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[N:26]=[CH:25]4)=[O:20])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[OH-:32].[K+]>CO.O>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]([NH:18][C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:32])=[O:4])[CH:10]=3)=[O:20])=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: [OH-]
Reactant: CNC(=O)c1cc(Oc2cccc(NC(=O)Nc3ccc4c(cnn4C)c3)c2)ccn1
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)O)c4)c3)ccc21
Temperature: 40 °C
Yield: 717.6 %

Procedure:
A mixture of N-methyl-4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)-phenoxy]pyridine-2-carboxamide (80 mg, 0.19 mmol) and powdered potassium hydroxide (0.03 g, 0.56 mmol) was dissolved in MeOH/H2O (4 mL, 3:1), and the reaction mixture was heated at 40° C. for 3 h. The solvent was removed in vacuo, the crude residue dissolved in H2O (5 mL), and precipitated on being neutralized with aq. 1N HCl. The precipitated solid was washed with water and then CH2Cl2 to give 0.55 g (70%) of the carboxylic acid. 1H-NMR (DMSO-d6) δ 9.97 (s, 1H), 9.77 (s, 1H), 8.46 (d, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.51 (d, 1H), 7.43-7.34 (m, 5H), 7.07 (dd, 1H), 6.73 (dd, 1H), 3.97 (s, 3H); MS LC-MS (M+H)+=404.1, RT=2.45 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:16](=[O:18])[CH3:17])[C:7]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:36]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][Br:36])[CH:13]=2)[N:8]([C:16](=[O:18])[CH3:17])[C:7]=1[C:19]([F:20])([F:21])[F:22])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(C)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(CBr)cc12
Temperature: 80 °C
Yield: 60.6 %

Procedure:
A mixture of (1-acetyl-5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (3.25 g, 9.94 mmol), AIBN (408 mg, 2.49 mmol) and N-bromosuccinimide (1.77 g, 9.94 mmol) in tetrachloromethane (50 mL) is heated to 80° C. for 2 h. After cooling to room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, cyclohexane/EtOAc 9:1) to afford the title compound as a yellow solid (2.44 g, 6.02 mmol, 61%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.88 (s, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 4.62 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.93 (s, 2H), 2.76 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). MS (ES+): 423 (M(C16H1579BrF3NO3)+H2O)+.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[CH:5][C:4]=1[F:31])#[N:2].[OH-:32].[Na+].Cl.[NH2:35]O>C(O)C>[NH2:2][C:1](=[N:35][OH:32])[C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:27][CH:28]=2)=[CH:5][C:4]=1[F:31]
Reactant: NO
Reactant: [OH-]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)c(F)c2)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)c(F)c2)cc1)C(C)C

Procedure:
A stirred solution of 4-[5-(4-cyano-3-fluoro-phenoxy)pentyloxy]-N,N-bis(1-methylethyl)benzamide (360 mg, 0.84 mmol) in 1.7 mL of 1N sodium hydroxide (1.7 mmol) and 10 mL of ethanol is treated with hydroxylamine hydrochloride (120 mg, 1.7 mmol). After refluxing overnight, the reaction is concentrated in vacuo. The resulting material is purified by chromatography on silica gel (500 g) with 60-70% ethyl acetate/hexane as the eluent to afford 4-[5-[4-[amino(hydroxyimino)methyl]-3-fluoro-phenoxy]pentyloxy]-N,N-bis (1-methylethyl)benzamide as a colorless foam;
Reaction SMILES: [CH2:1]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)(=[O:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:31][N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)(=[O:19])=[O:20]
Reactant: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
170 g of N-hexadecyl-3-nitro-4-chlorobenzenesulfonamide was dissolved in 640 ml of acetone, and 79 g of potassium carbonate, 4006 ml polyethylene glycol, and 71 g of dimethyl sulfate were added thereto, followed by refluxing the mixture for 5 hours under heating. Then, 240 ml of acetone was added thereto, and 870 ml of water was dropwise added thereto at 40° C. Upon cooling the mixture to room temperature, crystals were precipitated. The crystals were collected by filtration, washed with water and methanol successively, and then dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[N:12]O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ON=Cc1c[nH]c2ncnc(Cl)c12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (E-4) (865 mg, 4.40 mmol, 1.0 eq) in DCM (20 mL), thionyl chloride (3.1 mL, 43.7 mmol, 10.0 eq) is added and the resulting mixture is stirred at RT overnight. The reaction mixture is concentrated in vacuo. The residue is suspended in water (60 mL) and saturated aqueous NaHCO3 is added to adjust the pH to 4. The solid is collected by filtration, rinsed with water followed by ethyl acetate to afford a first portion of product. The filtrate is then extracted with ethyl acetate (50 mL×3). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is combined with the first portion of product. The product is then re-crystallized in ethyl acetate/hexanes (1:1) and dried in vacuo to afford the final product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (E-5) as a pale solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]#[N:18])[CH:11]=1.[OH-].[Na+]>CO>[C:17](/[C:16](/[C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1)=[CH:6]\[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:18]
Reactant: N#CCc1cccnc1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#C/C(=C\c1ccc(O)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (0.5 g, 4.1 mmoles), 3-pyridylacetonitrile (0.54 ml, 4.1 mmoles) and 50% w/v of aqueous NaOH (3.3 ml) in methanol (10 ml) was stirred at room temperature for 30 minutes. The yellow precipitate that formed was filtered, washed with cooled methanol (1 ml), cooled CH2Cl2 (10 ml), and dried under vacuum over P2O5 to yield 0.6 g (66%) of the title compound. 1H-NMR (CD3OD) 8.8 (d, 1H), 8.4 (m, 1H), 8.05 (m, 1H), 7.8 (m, 2H), 7.6 (s, 1H), 7.4 (m, 1H), 6.6 (m, 2H). 13C-NMR (DMSO) 177.52, 175.57, 146.59, 145.06, 144.78, 133.15, 132.73, 130.97, 123.8, 120.8, 120.3, 114.3, 88.5; Mass Spectrum m/e (M+1) 223.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[CH3:12].N1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:20]Cl>CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:14]1[CH:20]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:7]=[C:6]2[CH3:12]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: ClCCl
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: Cc1nn(-c2ccccc2)c2ccc(Br)cc12
Temperature: 25 °C

Procedure:
The mixture of 5-bromo-3-methyl-1H-indazole hydrochloride (999 mg), Cu(OAc)2 (1.13 g), pyridine (978 ul) and phenylbronic acid (982 mg) in dichloromethane (20 ml) was stirred at room temperature for over night. The mixture was filtered with celite pad, and the filtrate was evaporated under reduced pressure. The green residue was purified by silica gel chromatography (hexane/EtOAc) to give the intended compound as brown oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:22][C:23](=[O:34])[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](O)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:25](=[O:26])[CH:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:34])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)C(C(=O)OCc1ccccc1)c1ccccc1
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)C(C(=O)OCc1ccccc1)c1ccccc1

Procedure:
The experimental protocol used is the same as that described for intermediate 12.2, starting from N1-phenyl-1,4-benzenediamine and 3-(benzyloxy)-3-oxo-2-phenylpropanoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:36])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53])=[N+](C)C)C>>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:36])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[CH2:30][CH2:31][C:32]([O:34][N:51]1[C:56](=[O:57])[CH2:55][CH2:54][C:52]1=[O:53])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)NCCCOCCOCCOCCCNC(=O)CCC(=O)O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCC(=O)NCCCOCCOCCOCCCNC(=O)CCC(=O)ON1C(=O)CCC1=O

Procedure:
7-[3-(2-{2-[3-(3-Carboxypropionylamino)-propoxy]-ethoxy}-ethoxy)-propylcarbamoyl]-heptanoic acid tert-butyl ester (0.78 g, 1.46 mmol) was activated by means of TSTU as described in example 8 step 4. Crude yield 360 mg, LCMS Method 6: Rt 4.40 min; m/z (M+1) 630; Calcd.: 630. The compound was used without further purification.
Reaction SMILES: [CH2:1]([S:13][C:14]1[CH:31]=[CH:30][C:29]2[C:28](=[O:32])[C:27]3[C:18](=[C:19](Cl)[C:20]4[C:25]([C:26]=3Cl)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17](=[O:35])[C:16]=2[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:43](=[O:46])([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1>[CH2:1]([S:13][C:14]1[CH:31]=[CH:30][C:29]2[C:28](=[O:32])[C:27]3[C:18](=[C:19]([O:46][C:43]4[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:20]4[C:25]([C:26]=3[O:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17](=[O:35])[C:16]=2[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSc1ccc2c(c1)C(=O)c1c(c(Cl)c3ccccc3c1Cl)C2=O
Reactant: Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCCCCCCCCCCCSc1ccc2c(c1)C(=O)c1c(c(Oc3ccccc3)c3ccccc3c1Oc1ccccc1)C2=O
Yield: 106.4 %

Procedure:
0.20 g (0.38 mmol) of 2-n-dodecylthio-6,11-dichloronaphthacene-5,12-dione, 0.09 g (0.95 mmol) of phenol, 0.21 g (1.52 mmol) of potassium carbonate and 2 ml of DMSO are stirred for 75 minutes at 60° C. The mixture is taken up in toluene and extracted twice with toluene. The toluene phases are washed twice with water, dried over sodium sulfate and concentrated by evaporation. Recrystallisation from ether/pentane gives 0.13 g (54%) of the title compound A, m.p. 165°-8° C.; MS: 642 (M+ ; base peak).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[O:9]1[CH2:13][CH2:12]OC1=O.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:12][CH2:13][OH:9])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 4-bromo-1H-pyrazole in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel, eluants EtOAc and DCM 10%, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34%. 1H NMR (400 MHz, chloroform-D) δ ppm 7.49 (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:15][O:14][C:12]([C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:8]=[C:9]([CH3:11])[CH:10]=2)[C:2]=1[NH:1][C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13]
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2cc(C)nn2c1NC(=O)Cc1ccccc1
Temperature: 80 °C

Procedure:
A 250 mL round-bottomed flask containing methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (1.10 g, 5.0 mmol, 1 eq.), CH2Cl2 (40 mL), and Et3N (2.04 g, 20 mmol, 4 eq.) was added slowly phenylacetyl chloride (6.16 g, 40 mmol, 8 eq.). Then the mixture was heated at 80° C. for 4 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (40 mL) and water (25 mL). The aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic solution was dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography using MeOH and CH2Cl2 as the mobile phases to furnish Compound (20-1) as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:24]
Reactant: O=C(Cl)c1cccs1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccs4)cc3c2C1
Yield: 62.1 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.082 mMol) 2-thienoyl chloride, 9.7 mg (62%) of the title compound were recovered as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1.CC(C)(O)[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]1[C:17]#[N:18]
Reactant: O=C1CCC=C1CCCCCCCO
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCCCO
Yield: 68.5 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)-2-cyclopenten-1-one (17 g., 0.087 mole), acetone cyanohydrin (8.5 g., 0.1 mole), 6% aqueous sodium carbonate (8 ml.) and methanol (50 ml.) was stirred and heated under reflux for 4 hours. Methanol was removed in vacuo, water (100 ml.) was added and the mixture was extracted with diethyl ether and dried over magnesium sulphate. The solvent was removed by evaporation, and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (13.3 g., 68%), b.p. 144°-182°C./0.15 mm.Hg, nD25 1.4795.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12](=[O:23])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=3)=[CH:9][C:8]=2[CH:24]=1)([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO>[OH:23][CH:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:24][C:8]=2[CH:9]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=1
Reactant: CC(C)c1ccc2oc(C(=O)COc3ccc(C=O)cc3)cc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1ccc2oc(C(O)COc3ccc(CO)cc3)cc2c1
Yield: 90 %

Procedure:
5-Isopropyl-2-(4-formylphenoxyacetyl)benzofuran (18.1 g) was dissolved in 200 ml of methanol. Sodium borohydride (2 g) was added thereto with stirring and cooling with ice and the mixture was stirred for 1 hour. The reaction mixture was poured into aqueous solution of hydrochloric acid and the crystals separated out therefrom were collected by filtration followed by recrystallization from ethyl acetate/n-hexane to give 16.5 g of crystals. M.p. 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1C
Yield: 92 %

Procedure:
To 5-chloro-2-methyl-4-nitrobenzoic acid (900 mg, 4.15 mmol) in methanol (10 mL) was added thionyl chloride (0.3 mL, 4.15 mmol) dropwise. The mixture was heated to reflux for 5 h and then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give methyl 5-chloro-2-methyl-4-nitrobenzoate (880 mg, 92%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=230 at 4.25 min. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.73 (s, 1H), 3.95 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][S:18]3(=[O:24])=[O:23])[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].CCO>C1COCC1>[O:24]=[S:18]1(=[O:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][N:4]2[CH2:1][CH3:2]
Reactant: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2C(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1CCc2c1cc(C(=O)OC)cc2N1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
To a solution of methyl 1-acetyl-4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate (D235) (300 mg, 0.85 mmol, 1 equiv) in THF (20 ml) at room temperature was added BH3 (1.5 M in THF, 2 ml, 3 mmol, 3.5 equiv) and the resulting mixture was stirred at room temperature for 15 h. EtOH (5 ml) was added and the resulting mixture was concentrated in vacuo after 5 min. The residue was partitioned between a 2N aqueous HCl solution (20 ml) and CH2Cl2 (20 ml) and the biphasic mixture was vigorously stirred for 3 h. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 1/2) gave methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1-ethyl-2,3-dihydro-1H-indole-6-carboxylate (B145) (200 mg, 70%) as a very pale yellow solid. [M+H]+=339.2, RT=2.92 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]3[C:21]([O:23]C(C)(C)C)=[O:22])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:28][C:29]([NH2:31])=[NH:30])=[N:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]3[C:21]([OH:23])=[O:22])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:28][C:29]([NH2:31])=[NH:30])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCCC[C@@H]3C(=O)O)cc12
Yield: 155.1 %

Procedure:
A solution of tert-butyl (2R)-1-({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)-2-piperidinecarboxylate (50 mg, 0.107 mmol) in EtOAc saturated with HCl (10 ml), was stirred at room temperature for 2 h. The solution was concentrated in vacuo, and azeotroped several times with CH2Cl2, to give (2R)-1-({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)-2-piperidinecarboxylic acid hydrochloride (37 mg, 0.083 mmol) as a white solid.