Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[NH:14][N:13]=[CH:12]2)[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:21](=[O:22])C1.C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][CH:47]([C:50]2[C:51](=[O:60])[NH:52][C:53]3[C:58]([CH:59]=2)=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:46][CH2:45]1>CN(C)C=O>[CH3:18][C:16]1[CH:17]=[C:9]([CH2:8][C@@H:3]([NH:2][C:21]([N:44]2[CH2:45][CH2:46][CH:47]([C:50]3[C:51](=[O:60])[NH:52][C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:48][CH2:49]2)=[O:22])[C:4]([O:6][CH3:7])=[O:5])[CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2
Reactant: COC(=O)[C@H](N)Cc1cc(C)c2[nH]ncc2c1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate hydrochloride (7.26 g, 27.0 mmoles) in dimethylformamide (50 mL) at room temperature was added N,N′-disuccinimidyl carbonate (7.60 g, 29.7 mmoles) followed by triethylamine (11.29 mL, 81 mmoles). The resulting mixture was stirred for 30 min and treated with 3-(piperidin-4-yl)quinolin-2(1H)-one (6.77 g, 29.9 mmoles) in portions. The reaction was allowed to stir for 24 h. The mixture was concentrated, dissolved in ethyl acetate, and washed sequentially with water, brine, and 0.5 N HCl (2×). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (silica gel, 20:1 ethyl acetate/methanol) to give 11.9 g (78%). 1H-NMR (CD3OD) δ 13.0 (s, 1H), 11.8 (s, 1H), 7.98 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 7.45-7.41 (m, 2H), 7.27 (d, J=8.2Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J=7.9 Hz, 1H), 4.31-4.26 (m, 1H), 4.10-4.08 (m, 2H), 3.60 (s, 3H), 3.07-3.01 (m, 2H), 2.93-2.88 (m, 1H), 2.77-2.67 (m, 2H), 2.48 (s, 3H), 1.78-1.72 (m, 2H), 1.34-1.26 (m, 2H). Mass spec.: 488.52 (MH)+.
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:8][C:3]1([C:1]#[C:2][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:26][CH3:27])/[C:13](=[O:19])[NH:14]3)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC1(O)CCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCC3)c21

Procedure:
Using Method D above, 1-ethynyl-cyclopentanol (86.3 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.31 mmol) (Starting Material 1 above) using DPPFPdCl2 (12.6 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 2 days to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 40%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:18]#[N:19])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:18]([C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][N:10]=1)#[N:19]
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-phenylpyridine N-oxide (25 g, 0.146 mmol) in dichloromethane (200 ml) at room temperature was added trimethylsilyl cyanide (17.4 g), followed by the slow addition of dimethyl carbamyl chloride (16.2 ml) in dichloromethane (50 ml) over a 30 minute period. The reaction mixture was stirred at room temperature for one day, and then to it potassium carbonate solution (10%,150 ml) was added slowly. Stirring continued for an additional 30 minutes, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The extracts were combined and dried over magnesium sulfate. Evaporation in vacuo gave a crude reaction product (35 g) as a white solid. It was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][Br:8])([O-:3])=[O:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Br-:8].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Yield: 70.4 %

Procedure:
A suspension of 3-nitrobenzyl bromide (10 g, 46 mmol) in acetonltrile (100 ml) was added to a solution of triphenylphosphine (13.3 g, 51 mmol) in acetonitrile (150 ml). The resulting suspension was heated at reflux (15 min), cooled and 15.5 g of (3-nitrobenzyl)triphenylphosphonium bromide was obtained by filtration. A mixture of this compound (10 g, 21 mmol) and imidazole-2-carboxaldehyde (2 g, 21 mmol) was heated at reflux in ethanol (200 ml) and a solution of sodium ethoxide in ethanol (sodium (480 mg, 21 mmol; ethanol (100 ml)) was added dropwise over 2 h. After a further 3 h at reflux the solution was cooled, filtered and the solvent evaporated. The residue was taken up in 2M HCl (50 ml). The aqueous phase was washed with diethyl ether (3×50 ml), basified with 1N sodium hydroxide solution and the product extracted into diethyl ether (3×50 ml). The organic phase was dried (NaSO4) and evaporated to afford 4 g of a crude cis/trans mixture of 2-((3-nitrophenyl)ethen-2-yl)imidazole as a yellow solid. This material (1.75 g, 8.14 mmol) was dissolved in a mixture of dichloromethane (40 ml) and acetonitrile (40 ml) and di-t-butyl dicarbonate (2.13 g, 9.8 mmol) was added. After 48 h at room temperature the solvent was evaporated and the residue chromatographed on silica gel with ethyl acetate:petrol (bp 60°-80°) (1:1) as eluant to afford 1.7 g of a cis/trans mixture of the titled compound as a yellow oil. 1H NMR (250 MHz, CDCl3) δ 1.64 and 1.70 (9H, 2s), 6.72-8.50 (8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(Br)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cccc(Br)c1
Solvent: CCBr
Product: CCOP(=O)(Cc1cccc(Br)c1)OCC

Procedure:
50 g (0.2 mol) of 3-bromobenzyl bromide and 33.2 g (0.2 mol) of triethyl phosphite were heated at 140° C. for 2 hours, during which ethyl bromide was distilled off. The product was distilled over a 30 cm Vigreux column.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)[C:21](Cl)=[O:22].[I:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[C:28]=1C(O)=O>C(Cl)(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:21](=[O:22])[C:35]4[CH:34]=[C:33]([O:36][CH3:37])[C:32]([O:38][CH3:39])=[CH:28][C:27]=4[I:26])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Reactant: COc1ccc(I)c(C(=O)O)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Yield: 71 %

Procedure:
Prepared from N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylethane-1,2-diamine (1.0 g, 3.84 mmol) in 71% yield with a reaction time of 3 h, from the acid chloride prepared using 10 mmol of oxalyl chloride and 4.8 mmol of 2-iodo-5,6-dimethoxybenzoic acid. Compound 7a had: IR (CHCl3) 1652; 1H NMR (CDCl3) δ2.74 (s, 6H), 2.66 (t, 2H, J=7.0), 3.33 (s, 3H), 3.74 (s, 3H), 3.96 (m, 1H), 4.49, (m, 1H), 6.15 (s, 2H), 6.41 (s, 1H), 7.03 (s, 1H), 7.34 (d, 1H, J=4.8), 7.37 (s, 1H), 7.44 (s, 1H), 8.56 (d, 1H, J=4.8); 13C NMR (CDCl3) δ45.7, 46.9, 55 56.1, 56.6, 82.7, 98.5, 102.2, 106.7, 110.2, 120.2, 121.5, 122.9, 121.5, 122.9, 133.8, 145.9, 148.0, 148.3, 148.5, 149.0, 149.6, 151.0, 170.0; HRMS calcd for C23H24IN3O5H: 550.0839; found 550.0823.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 99.8 %

Procedure:
4-(4-Nitrophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (20 g, 65 mmol) was dissolved in anhydrous ethanol (250 mL) and 10% Pd/C (1.8 g) was added. The mixture was stirred for 1.5 h under 10 psi of hydrogen and filtered through a Celite pad. The pad was washed with ethyl acetate (3×100 mL) and the combined solution was evaporated in vacuo to yield 4-(4-amino-phenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (18 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[N+:24]([C:23]1[C:18]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Yield: 23 %

Procedure:
(R)-5-Amino-3-(pyrrolidin-2-ylmethyl)indole and 2-chloro-3-nitropyridine were used. Sodium acetate was used as base, acetic acid was used as solvent, and the reaction was heated at reflux (116°0 C.) for 2 hours. Column chromatography afforded the title compound (23%) as a dark red foam: 1H NMR (CDCl3) δ 10.05 (br s, 1H), 9.23 (br s, 1H), 8.49 (dd, J=1.8 and 8.3 Hz, 1H), 8.39 (1.8 and 4.5 Hz, 1H), 7.70 (d, J=1.7 Hz,1H), 7.33-7.22 (m, 2H), 6.98 (s,1H), 6.73 (dd, J=4.5 and 8.3 Hz, 1H), 3.46-3.34 (m, 1H), 3.10-2.97 (m, 1H), 2.97-2.78 (m, 3H), 1.99-1.64 (m, 3H), 1.56-1.42 (m, 1H); 13C NMR (CDCl3) δ 155.7, 151.5, 135.5, 134.5, 129.2, 128.1, 127.8, 123.8, 119.4, 114.3, 113.0, 111.6, 59.5, 45.7, 31.3, 30.6, 24.7; FAB LRMS (m/z, relative intensity) 338 (6, [MH+ ]), 309 (12), 155 (49), 135 (38), 119 (100). Anal. calcd for C18H19N5O2.0.67 C2H4O2 [acetic acid]: 61.53; H, 5.79; N, 18.56. Found: C, 61.57; H, 5.74; N, 18.82.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH-].[K+].CS(C)=O.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C.O>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cccc(OCCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (4.15 g, 33.98 mmol), KOH (4.93 g) and DMSO (50 ml) was added N-(2-chloroethyl) pyrrolidine hydrochloride (6.94 g). The reaction mixture was stirred at room temperature overnight, then was poured into water (750 ml) and ethyl acetate (350 ml) was added. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water (2×1000 ml), dried over MgSO4, filtered and stripped to afford 7.12 g of 3-[2-(1-pyrrolidinyl)ethoxy]benzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A dry 10 gallon glass-lined vessel was charged with the alcohol (2) (3.39 kg d.b., 18.1 Mol) and ethyl acetate (50 l) under nitrogen. The solution was cooled to -5° C. and triethylamine (Lancaster B/N 076337, 5.1 l) was added in one portion. Methanesulphonyl chloride (Lancaster B/N 79561, 1.68 l, 21.7 Mol) was added dropwise over 1 h, maintaining the reaction temperature at -5°-2° C. On complete addition, the slurry was aged at -5° C. for 30 min. Water (20 1) was added over 10 min and the phases well mixed The aqueous layer was separated and the organics washed with 1M aqueous hydrochloric acid (10 l), saturated sodium bicarbonate (10 1) and dried (Na2SO4). Solvent evaporation gave the product as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C(=[NH:51])(C1C=CC=CC=1)C1C=CC=CC=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:37][C:33]1[CH:32]=[C:31]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([NH2:51])[CH:3]=3)[N:7]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:6]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(N)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 2.0 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole obtained in Production Example II-9-c in 20 ml toluene at room temperature were added 0.73 g of benzophenoneimine, 95 mg of tris(dibenzylideneacetone)(chloroform)dipalladium(0), 0.17 g of 2,2′-bis(diphenylphosphino)-.1,1′-binaphthyl and 0.53 g of sodium tert-butyrate, and the mixture was heated under reflux for one day. The mixture was diluted with water and ethyl acetate, and the organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 30 ml of tetrahydrofuran, 10 ml of 5 N hydrochloric acid was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:3), and the resulting obtained crystals were washed with diethyl ether, to give 0.86 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[N:29]=[N:30][NH:31][CH:32]=2)=[CH:21][CH:20]=1.[BrH:33].C(O)(C)C>CO.ClCCl>[BrH:33].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[NH:29][N:30]=[N:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Agent: Br
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4cnn[nH]4)cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (20 mg, 0.046 mmol) in 1:1 methanol/dichloromethane (0.6 mL) was added dropwise 0.5 M hydrobromic acid in isopropanol (0.28 mL, 0.14 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, acetonitrile (0.6 mL) was added and the resulting slurry stirred at room temperature overnight. The solid was filtered and dried to give the title compound (0.6 g, 98%) as a solid which was characterized by XRPD. FIG. 3 shows a characteristic X-ray powder diffraction (XRPD) pattern of amorphous N-{[(5S)-3-(2-fluoro-4′-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide monohydrobromide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCSc1ccncc1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2-thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5%, colorless powder). mp: 86.0°-87.0° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)ccc1F
Temperature: 85 °C
Reaction time: 13 h
Yield: 91.8 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (32 g, 0.2 mol) in pyridine (100 mL) was added malonic acid (43 g, 0.4 mol) and piperidine (3 mL, 0.03 mol). The reaction solution was stirred at 85° C. for 13 hr. Upon cooling, the resulting suspension was added to cold water (500 mL) and acidified with conc. HCl (80 mL). The white solid was filtered off, washed with water and dried to yield 36 g (92%) of 3-(4-fluoro-3-methoxyphenyl)-acrylic acid. RP-HPLC: 3.71 min. 1H-NMR (DMSO-d6) δ (ppm) 3.85 (s, 3), 6.53 (d, 1, J=16), 7.20 (m, 2), 7.50 (m, 1), 7.52 (d, 1, J=16).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromobenzene-1-sulfonyl chloride (256 mg, 1.00 mmol) in 1 mL of dichloromethane was slowly added to a vial (40 mL) containing 5 mL of a saturated aqueous solution of sodium bicarbonate, dichloromethane (5 mL) and 1-methylpiperazine (100 mg, 1.00 mmol). The reaction was stirred at room temperature overnight. The phases were separated and the organic layer was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the required product, which was used in the next step without further purification. ESI-MS m/z calc. 318.0. found 318.9 (M+1)+. Retention time of 1.30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 3.03 (t, J=4.2 Hz, 4H), 2.48 (t, J=4.2 Hz, 4H), 2.26 (s, 3H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.Cl>[OH-].[K+].O>[CH:4]1[CH:2]=[C:2]2[CH:4]=[C:6]3[C:11](=[N:1][C:8]2=[CH:7][CH:6]=1)[CH:10]=[CH:9][CH:8]=[CH:7]3
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2nc3ccccc3cc2c1

Procedure:
The isatin product from step (a) was refluxed in 300 mL of 10% KOH solution in water for ca. 48 h. The solution was cooled and acidified to pH 2-3 with HCl. The yellow solid was suction filtered after 1 h and then washed with water. The solid was air-dried over night, washed with CH2Cl2 and then air-dried yielding 23.76 g of the acridine acid. 1H NMR (DMSO-d6) δ 7.72-8.30 (m, 7H).
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.S(Cl)([Cl:14])=O.ClCl.S1C2C=CC=CC=2C=N1>ClC1C=CC=CC=1>[Cl:14][C:5]1[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2][N:6]=1
Reactant: CSc1ccccc1C=NO
Reactant: O=S(Cl)Cl
Agent: ClCl
Agent: c1ccc2sncc2c1
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Yield: 96.1 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 33.4 g (0.2 mol) of 2-(methylthio)benzaldehyde oxime was added under nitrogen atmosphere. 25.2 g (0.21 mol) Of thionyl chloride was added dropwise thereto while stirring at a temperature of from -10° to -15° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, 15.6 g (0.22 mol) of chlorine was continuously blown into the reaction mixture containing 1,2-benzisothiazole while stirring at a temperature of from 70° to 80° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the reaction mixture was subjected to distilling off of the solvent and then to distillation under reduced pressure to give 32.6 g of 3-chloro-1,2-benzisothiazole. The yield was 96% to the 2-(methylthio)benzaldehyde oxime.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(CC)CC.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCOC(C)=O>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (70 mg, 0.3 mmol) in THF (3 mL) were added Et3N (0.105 mL, 0.76 mmol) and pivaloyl chloride (38 μL, 0.31 mmol). The reaction mass was stirred at rt for 2 h, diluted with EtOAc and was washed with water, and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.15 (br t, 1H), 7.43-7.35 (m, 2H), 4.38 (q, J=7.2 Hz, 2H), 4.26 (d, J=5.7 Hz, 2H), 1.30 (t, J=6.9 Hz, 3H), 1.11 (s, 9H).