Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=4)[CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:13][C:8]=3[N:7]([CH3:29])[S:6]2(=[O:31])=[O:30])[CH2:3][CH2:2]1.C(Cl)[Cl:33].Cl.CCOC(C)=O>CO>[ClH:33].[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[C:16]([CH2:17][NH2:18])[CH:26]=[CH:27][CH:28]=4)=[CH:13][C:8]=3[N:7]([CH3:29])[S:6]2(=[O:30])=[O:31])[CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: CN1c2cc(-c3cccc(CNC(=O)OC(C)(C)C)c3)ccc2N(CC2CC2)S1(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1c2cc(-c3cccc(CN)c3)ccc2N(CC2CC2)S1(=O)=O
Temperature: 25 °C

Procedure:
To a round bottom flask was added tert-butyl {3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]benzyl}carbamate (23-1) (0.250 g, 0.564 mmol), DCM (2 mL), MeOH (2 mL), and finally a saturated solution of HCl in EtOAc (4N) (0.705 mL, 2.82 mmol). The reaction mixture was then capped and permitted to stir at room temperature for an hour at which point it was concentrated to give 1-{3-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]phenyl}methanamine hydrochloride (23-2) as a waxy pink solid. HRMS (M+H)+: observed=344.1429, calculated=344.1427.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH2:20])[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(Cl)CCl.O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:30](=[O:31])[CH2:29][NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc(N2CCC(N3CC[C@@H](N)C3)CC2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C3)CC2)cc1
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of (3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-amine (HCl salt, 1.2 g, 3.13 mmol), [(tert-butoxycarbonyl)amino]acetic acid (727 mg, 4.15 mmol) in 40 mL pyridine was added EDC (1.06 g, 5.5 mmol). After 16 hours at room temperature, water (10 mL) and CH2Cl2 (10 mL) were added and the organic layer was washed with brine, dried over Mg2SO4, filtered and concentrated. The crude mixture was subjected to flash chromatography to afford tert-butyl [2-({(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]carbamate (812 mg, 62%). To a solution of tert-butyl [2-({(3R)-1-[1-(4-methoxyphenyl)piperidinyl)pyrrolidin-3-yl}amino)-2-oxoethyl]carbamate (1.00 g, 2.31 mmol) in CH2Cl2 (10 mL) was added 4N HCl/dioxane (10 mL). After 2 hours, ether was added and 2-amino-N-{(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}acetamide (1.02 g, quant.)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:23]2[N:24]=[CH:25]C=CC=2N=N1.C(N(CC)CC)C.CNC>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:24]([CH3:25])[CH3:23])=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)ccc1N
Reaction time: 0.08 h
Yield: 98 %

Procedure:
2-Amino-5-iodobenzoic acid (5.0 g, 19 mmol) was dissolved in dichloromethane (100 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.9 g, 21 mmol) and triethyl amine (2.1 g, 21 mmol) were added with magnetic stirring. After 5 min., dimethyl amine (2 N in THF, 19 mL, 38 mmol) was added and the resulting solution was stirred overnight. The reaction solution was washed with aqueous saturated sodium chloride and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 2-amino-5-iodo-N,N-dimethyl-benzamide (5.4 g, 98% yield) as yellow solids. MS: m/z 291 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)C.[H][H].[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[NH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1nnc(-c2ccc([N+](=O)[O-])c(OC)c2)[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1nnc(-c2ccc(N)c(OC)c2)[nH]1

Procedure:
50 mg of Pd/C were added to the solution of 200 mg of ethyl [5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetate in 100 ml of ethanol and hydrogen was introduced into the mixture at room temperature until the theoretical amount had been taken up. The catalyst was then removed by filtration and the filtrate was concentrated.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=[CH:5][N:6]([CH3:8])C.[NH2:24][C:25]1[NH:29][N:28]=[CH:27][C:26]=1C#N>C(O)(=O)C.C(OCC)(=O)C.CCCCCC>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3](=[O:23])[N:29]3[N:28]=[CH:27][C:26]([C:25]#[N:24])=[C:8]3[NH:6][CH:5]=2)=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(=CN(C)C)c1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1cn[nH]c1N
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cnn2c(=O)c(-c3ccc(OCc4ccccc4)cc3)c[nH]c12
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of 1.21 g (3.9 mmol) of 2-(4-benzyloxy-phenyl)-3-dimethylamino-acrylic acid methyl ester and 0.422 g (3.9 mmol) of 5-amino-1H-pyrazole-4-carbonitrile in 5 mL of acetic acid (HOAc) was heated at reflux overnight, during which time a precipitate formed. The reaction mixture was cooled to rt, diluted with 20% ethyl acetate in hexane solution, and filtered to give 0.86 g (65% over 2 steps) of 6-(4-benzyloxy-phenyl)-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a tan colored solid as indicated by 1H NMR; LC-MS—calcd for C20H14N4O2 [M++H]+: 343.11, found: 343.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:7]1[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: Fc1ccc2nn[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Fc1ccc2nnn(CCCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
6-fluoro-1H-benzotriazole (13.7 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method one for synthesis. The solution was separated and purified by HPLC to produce 8.9 g of 1-(4-chlorobutyl)-6-fluoro-1H-benzotriazole, with a yield of 39.0%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7.0 g (0.045 mol) of 3-fluoro-4-nitrophenol and 6.7 g (0.067 mol) of triethylamine in 20 ml of methylene chloride cooled to 0° is added 6.5 g (0.054 mol) of pivaloyl chloride in a dropwise manner. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over magnesium sulfate. Filtration and removal of the solvents gives crude 2-fluoro-4-pivaloyloxy-nitrobenzene which is dissolved in 200 ml of absolute ethanol. To the solution is added 0.9 g of 5% palladium on carbon, and the mixture is then hydrogenated under 30 psi hydrogen for two hours. The catalyst is filtered and the solvent removed to give 2-fluoro-4-pivaloyloxyaniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:21])=[CH:15]/[C:16](OCC)=[O:17])[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:21])=[CH:15]/[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C/C(=C\CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
A solution of ester 34 (4.10 g, 14.3 mmol) in anhydrous diethyl ether (40 mL) was added via cannula over 10 min to a slurry of lithium aluminum hydride (0.33 g, 8.6 mmol) in diethyl ether (100 mL) at 0° C. under argon. After 2 h, additional lithium aluminum hydride (0.13 g, 3.4 mmol) was added, and the mixture was stirred for 5 h. The reaction was quenched by sequential addition of H2O (0.46 mL), 15% aqueous sodium hydroxide (0.46 mL), and H2O (1.38 mL). The resulting slurry was filtered and the filtrate was concentrated in vacuo to give 3.8 g of a colorless oil. Purification by column chromatography (30:1 ratio silica gel/crude product; elution with 10% to 15% ethyl acetate/hexanes) provided 3.51 g (95%) of 35 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.35 (d, J=2 Hz, 1H, ArH), 7.28 (d, J=8 Hz, 1H, ArH), 7.18 (dd, J=2, 8 Hz, 1H, ArH), 5.95 (t, J=5 Hz, 1H, C=CH), 435 (t, J=5 Hz, 2H, CH2OH), 2.10 (s, 3H, CH3C=C), 1.65 (s, 4H, CH2CH2), 1.30 (s, 6H, 2×CH3), and 1.28 (s, 6H, 2×CH3).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]([CH3:24])[C:9]=32)=[CH:4][N:3]=1>[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[N:12]([CH3:24])[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2
Reactant: Cn1c2c(c(C(N)=O)c1-c1ccccc1)CCc1cnc(N)nc1-2
Agent: [Pd]
Product: Cn1c(-c2ccccc2)c(C(N)=O)c2ccc3cnc(N)nc3c21
Yield: 85 %

Procedure:
A suspension of 8-amino-1-methyl-2-phenyl-4,5-dihydro-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid amide N4 (0.25 mmol) and 10% Pd on carbon (50 mg) in 10 mL of xilene was heated to reflux for 15 days. The mixture was filtered through a celite pad and the solvent evaporated to dryness affording the title compound (85% yield). ESI (+) MS: m/z 318 (MH+). 1H NMR: 4.21 (s, 3H), 6.15 (bs, 1H), 6.76 (bs, 2H), 7.08 (bs, 1H), 7.42 (d, J=8.50, 1H), 7.52-7.65 (m, 5H), 7.83 (d, J=8.50, 1H), 9.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)([CH3:20])[NH:17][C:18](=[O:19])[C:12]3=[CH:11][CH:10]=2)[CH:3]=1.[H-].[Na+].[N:28]#[C:29]Br>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)([CH3:20])[N:17]([C:29]#[N:28])[C:18](=[O:19])[C:12]3=[CH:11][CH:10]=2)[CH:3]=1
Reactant: N#CBr
Reactant: CC1(C2CCCC2)NC(=O)c2ccc(Nc3cc(N)ncn3)c(=O)n21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C2CCCC2)N(C#N)C(=O)c2ccc(Nc3cc(N)ncn3)c(=O)n21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 2-neck round bottom flask 6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione (2, 0.28 g, 0.82 mmol) was taken in dry tetrahydrofuran (15 mL). The reaction mixture was cooled to 0° C. and sodium hydride (164 mg, 4.11 mmol) was added in portions. After stirring for 10 min at room temperature, cyanogen bromide (436 mg, 4.11 mmol) was added and the resulting reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with aqueous ammonium chloride solution and then concentrated to get the crude mass. This crude was purified by flash chromatography eluting with 2% methanol in dichloromethane. The compound was washed with pentane and dried under vacuum to afford 6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo[1,5-a]pyridine-2-carbonitrile (Cpd. No. 118) as yellow solid. Yield: 0.018 g, 6%; MS (ESI) m/z 366.16 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.71 (d, J=7.84, 1H), 8.19 (s, 1H), 7.28 (d, J=7.96, 1H), 6.65 (s, 2H), 6.29 (s, 1H), 3.49-3.43 (m, 1H), 2.21 (s, 3H), 1.94 (m, 1H), 1.7-1.58 (m, 4H), 1.48 (m, 1H), 1.23 (m, 1H), 1.06-1.02 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][N:33]1[CH:34]=[CH:35][C:31]([NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:29])=[N:32]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (93.12 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (54.1 mg, 47.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H35Cl2N5O2+H [(M+H)+]: 568.2241. found: 568.2246.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)(O)[CH2:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccncc2)CCC2(CCN(Cc3ccccc3)C2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2ccncc2)CCC2(C1)CCN(Cc1ccccc1)C2
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 2-benzyl-8-(pyridin-4-yl)-2-azaspiro[4.5]decan-8-ol (500 mg, 1.55 mmol, 1.0 eq.) (see step-7 product AMN-39) in pyridine (5 ml) was added dropwise SOCl2 (1 ml) at −10° C. and the reaction mixture was stirred at the same temperature for 10 min. After completion of the reaction (monitored by TLC), the reaction mixture was poured onto (50 g) and sat. NaHCO3 solution (10 ml) was added. The mixture was extracted with methylene chloride (50 ml). The organic layer was washed with brine (30 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield the desired compound as a yellow semisold. Yield: 63% (300 mg, 0.987 mmol).
Reaction SMILES: C([NH:9][C:10](=[O:37])[NH:11][C:12]1[O:13][C:14]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[C:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]=1[C:17](OCC)=[O:18])(=O)C1C=CC=CC=1.[O-]CC.[Na+]>CCO>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:15]2[C:16]3[C:17](=[O:18])[NH:9][C:10](=[O:37])[NH:11][C:12]=3[O:13][C:14]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1c(NC(=O)NC(=O)c2ccccc2)oc(-c2cccc(Cl)c2)c1Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc2[nH]1
Temperature: 25 °C
Yield: 5939.8 %

Procedure:
To a solution of ethyl 2-(3-benzoylureido)-4-(4-chlorobenzyl)-5-(3-chlorophenyl)furan-3-carboxylate (53.6 mg, 0.1 mmol) in EtOH (2 mL) was added sodium ethoxide (13.6 mg, 0.2 mmol). The reaction was heated at 100° C. (MW) for 20 min, cooled to RT and quenched with aq. NH4Cl (2 mL). The reaction was concentrated to a residue which was diluted with water (3 mL) and extracted with EA (3×8 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 5-(4-chlorobenzyl)-6-(3-chloro phenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.3 g, 83% yield) as a white solid. 1H NMR (DMSO-d6) δ: 9.70 (brd s, 1H), 7.38 (m, 3H), 7.33 (d, J=8.5 Hz, 2H), 7.30-7.21 (m, 3H), 4.24 (s, 2H). LCMS: MH+ 387 and TR=2.685 min. Used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31]>C1COCC1>[F:27][C:26]1[C:25]([F:28])=[CH:24][C:23]([F:29])=[C:22]([N+:30]([O-:32])=[O:31])[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (1.0 g, 4.21 mmol) in THF (20 mL) was dropwise added LHMDS solution (5.1 mL, 5.1 mmol, 1 M in THF) at −78° C. After stirring at −78° C. for 30 min, a solution of 2,3,4,6-tetrafluoronitrobenzene (0.823 g, 4.21 mmol) in THF (5 mL) was added drop wise into the reaction mixture, which was slowly warmed to room temperature and stirred for 16 h. After completion (as indicated by TLC), the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over anhydrous Na2SO4 and concentrated. The crude residue was triturated with hexane to yield 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitrobenzenamine (0.748 g). 1H-NMR (400 MHz, CDCl3): δ 6.71-6.76 (2H, m), 7.40 (1H, d, J=8.8), 7.46 (1H, d, J=10), 7.69 (1H, s).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:15][OH:16]>CO.C(OCC)(=O)C.[Pt].[Pt]=O>[CH2:1]([N:15]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NO
Reactant: CCCCCCCCCCCC=O
Agent: O=[Pt]
Agent: [Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 49.8 %

Procedure:
A solution of dodecanal (9.2 g, 50 mmol) and hydroxylamine hydrochloride (2.0 g, 29 mmol) in 70 ml of methanol and 10 ml of ethyl acetate is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for 2.5 hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (400 mg) and platinum oxide (15 mg). The reaction mixture is then worked up as described in Example 4 to give, after recrystallization from methanol, 4.6 g (50% yield) of the title compound as a white solid identical to that prepared in Example 4.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:15][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH3:11]
Reactant: CCOC(CN)OCC
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc(Cl)s1)OCC
Temperature: 4 °C
Yield: 64.8 %

Procedure:
Add 5-chlorothiophene-2-carboxylic acid (100 g, 0.60 mol) and dichloromethane (1000 mL) to a 3 L three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel, and thermocouple. Stir the resulting solution under nitrogen while cooling to 4° C. Add via addition funnel 2,2-diethyoxyethylamine (88.5 ml, 0.60 mol) in dichloromethane (35 mL) over 12 minutes. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 g, 0.64 mol) to the chilled mixture. Add additional dichloromethane (165 mL) and stir the reaction mixture for 22 h at room temperature. Quench the reaction with water (1000 mL) and separate the resulting layers. Back extract the aqueous layer with dichloromethane (500 mL) and combine the organic layers. Dry over sodium sulfate and purify through a silica gel bed eluting with dichloromethane followed by a mixture of 1% MeOH in dichloromethane and then a mixture of 10% MeOH in dichloromethane to afford 108 g (65%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.26 (d, J=3.5 Hz, 1H), 6.85 (d, J=3.5 Hz, 1H), 6.37 (bs, 1H), 4.57 (t, J=5.5 Hz, 1H), 3.68-3.74 (m, 2H), 3.48-3.57 (m, 4H), 1.19 (t, J=7.5 Hz, 6H).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([NH:32]C(=O)C)([CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16](C(OC(C)(C)C)=O)[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3)C(OCC)=O)C.Br>>[NH2:32][CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:16][C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)c1ccccc1n2C(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Agent: Br
Product: NC(Cc1ccc2[nH]c3ccccc3c2c1)C(=O)O

Procedure:
2-Acetylamino-2-(9-tert-butoxycarbonyl-9H-carbazol-3-ylmethyl)-malonic acid diethyl ester (200 mg, 0.4 mmol) was combined with hydrogen bromide (4 mL of a 24% aqueous solution) and refluxed for about 12 h. The cooled reaction mixture was evaporated under reduced pressure and dried under high vacuum to afford the amino acid as the hydrogen bromide salt. ES-MS (M+H)+ 255.0 (calc. 254.1).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([CH:6]([CH:15]=[CH2:16])[CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])[CH3:5]>O1CCCC1.CO.O>[CH2:15]([CH:6]([CH:4]=[CH2:5])[CH2:7]/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH3:16]
Reactant: C=CC(CC)C/C=C/C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CC(CC)C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (4.39 g, 104 mmol) was added to a tetrahydrofuran:methanol:water (3:3:1, 100 mL) mixed solution of ethyl (2E)-5-ethylhepta-2,6-dienoate (9.52 g, 52.2 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. To the residue, water was then added, followed by washing with diethyl ether. The aqueous layer was made acidic by the addition of 5 M hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain the compound of interest as an oil substance (8.00 g, >99%).