Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][NH:23][C:22]4=[O:26])[N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[C:36](=[O:39])([OH:38])[O-:37].[Na+]>O.CS(C)=O.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>[C:36](=[O:37])([OH:39])[O-:38].[NH4+:12].[Cl:17][C:16]1[C:11]([C:9]2[S:8][C:7]3[C:2]([C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)=[CH:3][CH:4]=[CH:5][C:6]=3[CH:10]=2)=[N:12][C:13]([NH:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])=[N:14][CH:15]=1
Reactant: O=C1NCCN1CCNc1ncc(Cl)c(-c2cc3cccc(Br)c3s2)n1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1CCNc1ncc(Cl)c(-c2cc3cccc(-c4ccncc4)c3s2)n1
Product: [NH4+]
Yield: 50.3 %

Procedure:
Combine 1-{2-[4-(7-bromo-benzo[b]thiophen-2-yl)-5-chloro-pyrimidin-2-ylamino]-ethyl}-imidazolidin-2-one (81.6 mg, 0.18 mmol), pyridine-4-boronic acid (36.8 mg, 0.3 mmol), and sodium bicarbonate (18.1 mg, 0.2 mmol) in a mixture of water (1 mL) and DMSO (1 mL). Add tetrakis(triphenylphosphine)palladium(0) (10.4 mg, 0.009 mmol). Irradiate the mixture at 150° C. for 15 min with magnetic stirring. Pour the crude reaction mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N ammonia in methanol (40 mL) and concentrate under reduced pressure. Purify by reverse phase chromatography (30 to 90% gradient at 80 mL/min for 11 min on a 30×100 mm, 5 mm, C18 MS Xterra® column, Solvent A: water with 0.01 M ammonium bicarbonate, Solvent B: acetonitrile) to afford the title compound (20.4 mg, 25.1%). MS (ES) m/z 451 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[CH:6]=[CH:7][CH:8]=1.O1[CH2:19][CH2:18]COO1.C=O.[CH2:22]([NH:24][CH2:25]C)[CH3:23].[OH-].[Na+]>O1CCOCC1.C(O)(=O)C.O>[CH2:22]([N:24]([CH2:18][CH3:19])[CH2:25][C:13]#[C:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:23]
Reactant: C#CCCCc1cccc(OC)c1
Reactant: C1COOOC1
Reactant: CCNCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CC#CCCCc1cccc(OC)c1
Yield: 736.2 %

Procedure:
Allow 5-m-methoxyphenylpent-1-yne (8 g) to stand for 12 hours at 70°C under nitrogen with water (2.5 cc), trioxan (0.5 g), 30% formalin (5.5 g), diethylamine (4 g), acetic acid (2.75 g), dioxan (25 cc) and cuprous chloride (0.13 g). Make the cooled solution alkaline with 10% aqueous sodium hydroxide and extract with ether; then extract the ether extract with 10% hydrochloric acid: wash the acid extract with ether, make alkaline with 10% aqueous sodium hydroxide, extract with ether, and then wash and dry the ether extract. Distil to obtain 1-diethylamino-6-m-methoxyphenylhex-2-yne (10.6 g, 88%), b.p. 130°-131°C/0.1 mm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:16])([F:15])[C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([NH2:32])([C:30]#[N:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][C:27]([C:30]#[N:31])([NH:32][C:12]([C:9]2([C:8]([F:16])([F:15])[F:7])[CH2:11][CH2:10]2)=[O:13])[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Oxalyl chloride (0.20 ml, 2.3 mmol) and dimethylformamide (8 μl) were added to a solution of 1-trifluoromethyl-cyclopropanecarboxylic acid (308 mg, 2.00 mmol) in dichloromethane (2.1 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure. A solution of the resulting residue in dichloromethane (1.5 ml) was added dropwise to a solution of 4-amino-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (377 mg, 1.67 mmol) and diisopropylethylamine (0.42 ml, 2.4 mmol) in dichloromethane (2.0 ml) over three minutes at 0° C., and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was then washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→2/1) to give 4-cyano-4-[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid (519 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:18]=[O:19])C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:18]=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: COc1cccnc1Cl
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C=O)ccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-chloro-3-methoxypyridine (1.55 g, 10.8 mmol, prepared as described in WO2007/123995) in dry THF (30 mL), cooled to −78° C., was added 2.5 M nBuLi in hexanes (4.75 mL, 11.9 mmol). After 1 hour, a solution of DMF (2.5 mL, 32.4 mmol) in THF (5 mL) was added. After a further 2.5 hours, a saturated aqueous ammonium chloride solution was added and the reaction mixture was allowed to warm to RT. The resultant biphasic mixture was separated and extracted twice with diethyl ether. The combined organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 20 to 25% ethyl acetate in cyclohexane) to afford the title compound (1.42 g, 77%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 10.44 (d, J=0.8 Hz, 1H), 8.34 (dd, J=4.9 and 0.8 Hz, 1H), 7.60 (d, J=4.9 Hz, 1H), 4.08 (s, 3H). LCMS (Method A): RT=2.84 min, [M+H]+=172/174.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2F)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2F)CC1
Yield: 175.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(R)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (4.825 g, 15.11 mmol) was dissolved in dry benzene (150 ml), and the solution was mixed with Lawesson's reagent (3.085 g, 7.625 mmol) and heated under reflux for 30 minutes. After cooling, benzene was evaporated under a reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=5:1, to thereby obtain 4.494 g (88.7%) of the title compound as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Cl:22][C:23]1[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:53]C([N-]C(C)C)C>>[Cl:22][C:23]1[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[CH:45][C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:53])=[CH:14][CH:13]=2
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: O=[N+]([O-])c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3Cl)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-chloro-3-nitrobenzyl)(triphenyl)phosphonium bromide (554) preared as described in example 143 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (555) as an orange crystalline solid (the pure E isomer) (50%), mp 131–133° C. 1H NMR (CDCl3) δ 8.24 (br s, 1H), 7.86 (dd, J=8.0, 1.4 Hz, 1H), 7.63 (dd, J=7.9, 1.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.25 (d, J=15.8 Hz, 1H), 7.15 (d, J=16.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.9, 2.4 Hz, 1H), 6.65 (d, J=1.7 Hz, 1H), 3.86 (s, 3H). Found: C, 61.97; H, 3.92; N, 8.50. C17H13ClN2O3 requires C, 62.11; H, 3.99; N, 8.52.
Reaction SMILES: [CH:1]1([N:4]2[CH:20]=[C:7]3[CH:8]=[C:9]4[C:17](=[N:18][C:6]3=[CH:5]2)[N:16]2[CH:11]([CH2:12][NH:13][CH2:14][CH:15]2[CH3:19])[CH2:10]4)[CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.O.[Pd]>[NH3:4].[CH:1]1([N:4]2[CH2:20][C:7]3=[CH:8][C:9]4[CH2:10][C@H:11]5[N:16]([C:17]=4[N:18]=[C:6]3[CH2:5]2)[C@H:15]([CH3:19])[CH2:14][NH:13][CH2:12]5)[CH2:3][CH2:2]1
Reactant: CC1CNCC2Cc3cc4cn(C5CC5)cc4nc3N12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1CNC[C@H]2Cc3cc4c(nc3N21)CN(C1CC1)C4
Product: N
Yield: 35.4 %

Procedure:
To a solution of 0.014 g 2-cyclopropyl-5-methyl-5,6,7,8,8a,9-hexahydro-2H-2,4,4b,7-tetraaza-cyclopenta[b]fluorene in 1.0 ml glacial acetic acid and 1.00 ml water was added 0.005 g palladium 10% on charcoal and the mixture stirred for 18 h under 1 atmosphere of hydrogen at room temperature. The solvents were evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:ammonia=90:10:1 to yield 0.0025 g of the title compound as slightly brownish oil (MS: 271.3 (M+H+)).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(F)c2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 50 mg (0.28 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 90 mg of TBTU (0.28 mmol) in 4 ml DMF, were added 0.24 ml (1.4 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 180 mg (0.28 mmol) acid of (4-tert-butyl-benzyl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (9 g silica gel; EtOAc/heptane 1:4) to give 85 mg light yellow foam (85%). MS 464.1 (M)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])=O)[N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.N.C[N:43](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>[C:37]([CH2:36][N:33]1[CH:34]=[CH:35][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[N:32]1)(=[O:39])[NH2:43]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC(=O)O)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(N)=O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-yl)-acetic acid (85 mg, 0.144 mmol), ammonia (0.57 mL, 0.288 mmol, 0.5 M in dioxane), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 109 mg, 0.288 mmol) and iPr2NEt (0.1 mL, 0.43 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (12.3 mg, 14.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C28H28Cl2F2N6O2+H [(M+H)+]: 589.1692. found: 589.1693.
Reaction SMILES: [S:1]1[CH2:6][CH2:5]C(C#N)[CH2:3][CH2:2]1.[OH-:9].[Na+].Cl.[CH2:12]([OH:14])[CH3:13]>O>[S:1]1[CH2:6][CH2:5][CH:13]([C:12]([OH:9])=[O:14])[CH2:3][CH2:2]1
Reactant: N#CC1CCSCC1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCSCC1
Yield: 60 %

Procedure:
A solution of 1.97 g (15.5 mmol) of tetrahydro-thiopyran-4-carbonitrile in 5 mL of ethanol (EtOH) was added to a solution of 6.2 g (155 mmol) of sodium hydroxide (NaOH) in 30 mL of EtOH and 15 mL of water, and the resulting mixture was heated at reflux for 4 h. The reaction mixture was cooled in an ice bath, acidified with concentrated hydrochloric acid to pH=2, and then concentrated to give a precipitate which was filtered to afford 1.36 g (60%) of desired tetrahydro-thiopyran-4-carboxylic acid as a brown crystalline solid as indicated by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](\[NH2:7])/[CH3:6].[C:9]1([S:15]([CH2:18][C:19](=O)[CH3:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)([O-:24])=[O:23]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)(=O)C>[CH3:6][C:5]1[NH:7][C:19]([CH3:20])=[C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:27]([C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N+:22]([O-:24])=[O:23])[C:4]=1[C:3]([O:2][CH3:1])=[O:8]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccccc2)C1c1ccccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 10 h

Procedure:
6.9 g of 3-aminocrotonic acid methyl ester and 13.9 g of phenylsulphonylacetone are added to 9.1 g of o-nitrobenz- aldehyde dissolved in 50 ml of hexamethylphosphoric acid triamide. The mixture is then stirred for 10 hours under nitrogen at a bath temperature of 110° C. The mixture is cooled and dissolved in 400 ml of ethyl acetate and the solution is washed with a mixture of 400 ml of water, 60 ml of methanol and 60 ml of saturated sodium chloride solution. The aqueous phase is separated off and the organic phase is washed with 3 times 100 ml of water, with twice 100 ml of 1 N hydrochloric acid solution, with twice 60 ml of saturated sodium bicarbonate solution and once with 60 ml of 2 N sodium carbonate solution. The ethyl acetate phase is dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel using a mixture of toluene and ethyl acetate (7:3) as the eluant. The eluate is evaporated and crystallised from methanol. In this way, 2,6dimethyl-3-carbomethoxy-4-(2-nitrophenyl)-5- phenylsulphonyl-1,4-dihydropyridine, of melting point 203° C, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12](=[O:27])[C:13]([CH3:26])=[CH:14][C:15]=1[C:16](ON1C(=O)CCC1=O)=[O:17].C1COCC1.CC(C)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12](=[O:27])[C:13]([CH3:26])=[CH:14][C:15]=1[C:16]([N:38]=[N+:39]=[N-:40])=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(=O)ON2C(=O)CCC2=O)c(Nc2ccc(I)cc2F)n(C)c1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)N=[N+]=[N-])c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A 100 ml round-bottom flask was charged with 2,5-dioxopyrrolidin-1-yl 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.2 g, 2.40 mmol) and a mixture of THF/acetone (15 mL/30 mL). To the mixture was added NaN3 (0.52 g, 8 mmol) is previously dissolved in H2O (10 mL). The reaction mixture was stirred art room temperature for 16 hours and the organic solvents were removed under reduced pressure yielding to the desired product as a light brown solid (0.98 g, 96%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=1
Reactant: CCOC(=O)c1csc(COCCOC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCc1nc(CO)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of ethyl 2-((2-methoxyethoxy)methyl)thiazole-4-carboxylate (Example 6C, 2.27 g, 9.25 mmol) in ether (50 mL) was added portion wise lithium aluminum hydride (1.06 g, 27.9 mmol) over 10 min. at −78° C. The reaction was then stirred at −78° C. for 1 hour. Ethyl acetate (10 mL) was then added to the reaction followed by water (20 mL) and the reaction was allowed to reach RT. The mixture was then diluted with ethyl acetate, washed with HCl 1N (1×) and brine (1×). The combined aqueous phases were extracted with ethyl acetate (2×300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3.5×10 cm, ethyl acetate) to give the title material (0.357 g, 19%) as a brown oil. LC (Method F): 1.791 min. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.16 (s, 1H), 4.82 (s, 2H), 4.74 (broad s, 2H), 3.7-3.75 (m, 2H), 3.54-3.61 (m, 2H), 3.38 (s, 3H), 2.28 (broad s, 1H).
Reaction SMILES: [Cl:1]C1C=CC=CC=1O.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:1])[C:11]=1[OH:17]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1Cl
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
The addition of ortho-chlorophenol was then stopped and the chlorination was continued until the orthochlorophenol present and the 2,4,-dichlorophenol had completely disappeared.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C@H:13]2[C@@H:17]3[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]3[C@@H:15]([O:23][CH2:24][CH2:25][OH:26])[CH2:14]2)[C:3]=1[N+:27]([O-])=O.C(O)(=O)C>[Fe].O.C(O)C>[NH2:27][C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]3[O:18][C:19]([CH3:21])([CH3:22])[O:20][C@@H:16]3[C@@H:15]([O:23][CH2:24][CH2:25][OH:26])[CH2:14]2)=[N:5][C:6]([S:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]=1[Cl:1]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 104.6 %

Procedure:
A suspension of 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (800 mg, 1.78 mmol, 1.00 equiv.), iron powder (800 mg, 14.29 mmol, 8.00 equiv.), acetic acid (860 mg, 14.33 mmol, 8.00 equiv.) and water/ethanol (10 mL) was stirred at about 60° C. for about 20 minutes in an oil bath. After the solids were removed by filtration, the resulting filtrate was extracted with dichloromethane (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a yellow oil (780 mg; yield=93%). MS: m/z=419 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH2:12])=[CH:5]2.[CH3:13]OC(OC)N(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][CH3:13])=[CH:5]2
Reactant: Nc1cc2cc(Br)ccc2cn1
Reactant: COC(OC)N(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc2cc(Br)ccc2cn1
Temperature: 110 °C
Yield: 43 %

Procedure:
To a solution of 6-bromoisoquinolin-3-amine (50.0 mg, 2.6 mmol) in N,N-dimethylformamide (10 mL) was added N,N-dimethylformamide dimethylacetal (2 mL). The reaction vessel was sealed and heated in a Biotage Smith Synthesizer microwave to 110° C. for 20 minutes. Sodium triacetoxyborohydride (59 mg, 0.28 mmol) was then added to the reaction mixture. The vial was resealed and heated again to 110° C. on a Biotage Smith Synthesizer microwave for 10 minutes. The reaction was concentrated. The residue was dissolved in ethyl acetate (50 mL) and washed with brine (2×20 mL). The organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (23 mg, 43%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.76 (s, 1H), 7.74 (s, 1H), 7.61 (d, 1H), 7.28 (d, 1H), 6.40 (s, 1H), 5.09-5.07 (m, 1H), 2.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Cl)CC1
Yield: 66.5 %

Procedure:
A mixture of 2-chloro-5-nitrobenzenamine (7.95 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (8.86 g) in chlorobenzene (40 ml) under nitrogen was heated to reflux for 3 days before cooling and diluting with dichloromethane (60 ml). The reaction mixture was then extracted with water (2×500 ml), the aqueous layers combined and basified with 2N sodium hydroxide, then extracted with dichloromethane (4×400 ml). The combined, dried extracts were concentrated in vacuo to give a dark brown oil (7.82 g) which was purified by flash column chromatography eluting with ether to give a dark brown oil which crystallised upon standing. The material was dissolved in ethanol (40 ml) and boiled up with some charcoal (300 mg). The hot ethanolic suspension was filtered and concentrated in vacuo to give the title compound as a yellow oil which crystallised on standing (5.25 g) m.p.63°-64° C.