Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[C:23](=[O:24])[C:22]2[C:14](=[CH:15][C:16]3[O:20][CH2:19][O:18][C:17]=3[CH:21]=2)[CH2:13]1)(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[C:23](=[O:24])[C:22]3[C:14](=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=3)[CH2:13]2)[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc3c(cc2C1=O)OCO3
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: CC(=O)C1=CN(Cc2ccccc2C)C=CC1CC1Cc2cc3c(cc2C1=O)OCO3

Procedure:
The title compound 165 is prepared according to the procedure reported in Example 39.1 with compound 139 (100 mg, 0.20 mmol) and BNAH (43 mg, 1 equiv) as reactants. Yellow solid. (Yield 32.1 mg, 38%).
Reaction SMILES: [NH2:1][OH:2].[Cl:3][C:4]1[C:5]([NH:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=1>C1COCC1>[NH2:11][C:10](=[N:1][OH:2])[C:8]1[CH:9]=[C:4]([Cl:3])[C:5]([NH:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNc1ncc(C#N)cc1Cl
Reactant: NO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ncc(C(N)=NO)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
Hydroxylamine (1.5 mL, 39.5 mmol) was added into a solution of tert-butyl [(3-chloro-5-cyanopyridin-2-yl)amino]acetate (2.1 g, 7.9 mmol) in THF (30 mL) under nitrogen. The reaction mixture was stirred at RT for 48 hours, and then was concentrated under reduced pressure to afford the title compound as a white solid (2.4 g, quantitative). LC/MS, M+(ESI): 301.0. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (1H, s), 8.24 (1H, d), 7.81 (1H, d), 7.04 (1H, t), 5.80 (2H, s), 3.95 (2H, m), 1.37 (9H, s).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][C:17](C(O)=O)=[CH:16][C@H:15]1[OH:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C[O-].[Na+]>CO>[CH3:5][O:4][C:2]([C:17]1[CH2:18][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:12])[C@H:15]([OH:22])[CH:16]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)O)=C[C@H]1O
Reactant: COC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1=C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Methyl chloroformate (29 /ml, 0.37 mol) was added dropwise to a cooled solution (0° C.) of (3R,4S)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid (83 g, 0.34 mol) and triethylamine (52 ml, 0.37 mol) in methanol (600 ml). The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature. After stirring for 14 h, it was apparent that the reaction was incomplete. After cooling to 0° C., triethylamine (30 ml, 0.22 mol) was added, and then methyl chloroformate (15 ml, 0.19 mol) was added dropwise. The reaction was complete after a further 2 h. The reaction mixture was concentrated under vacuum and the residue redissolved in dichloromethane (400 ml). The organic solution was washed sequentially with 1M potassium hydrogen sulfate (aq) (2×200 ml), saturated hydrogen carbonate (2×200 ml) and brine (200 ml) before drying over magnesium sulfate. Following filtration, the solvent was removed to yield an orange oil which was redissolved in methanol (300 ml) and cooled to 5° C. Sodium methoxide (0.25 ml, 25% wt solution in methanol, 3 mol %) was then added and the reaction mixture cooled and stirred for 4 h. The reaction was quenched with glacial acetic acid and concentrated under vacuum, and the residue was redissolved in dichlormethane (300 ml). The organic solution was washed with saturated sodium hydrogen carbonate (100 ml) then brine (100 ml) and dried over magnesium sulfate. Following filtration, the solvent was removed under vacuum to yield the title compound as an orange oil (76 g, 87%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(N(C(C)C)CC)(C)C.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Si:15]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution of 1,3-propanediol (4.22 g, 55 mmol) in anhydrous CH2Cl2 (10 mL) under argon was treated with diisopropylethyl amine (10 mL) and tert-butyldiphenylsilyl chloride (5.00 mL, 5.29 g, 19.23 mmol). Stirring was continued for 2 h. The sample was concentrated, and the residue was purified by column chromatography (silica, hexanes/ethyl acetate (10:1)] affording a colorless oil (4.74 g, 78%): 1H NMR δ 1.07 (s, 9H), 1.78-1.86 (m, 2H), 2.46-2.50 (m, 1H), 3.83-3.88 (m, 4H), 7.37-7.48 (m, 6H), 7.68-7.75 (m, 4H); 13C NMR δ 19.33, 27.08, 34.52, 62.11, 63.46, 128.01, 130.03, 133.50, 135.80; FAB-MS obsd 315.1779, calcd 315.1780 [(M+H)+, M=C19H26O2Si].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:33]([CH3:35])[CH3:34])[NH:11]1.[CH2:36]([NH:38][CH2:39]C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH:31]=[CH:32][N:38]([CH3:39])[CH3:36])(=[O:30])=[O:29])=[CH:25][CH:26]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:33]([CH3:35])[CH3:34])[NH:11]1
Reactant: C=CS(=O)(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NS(=O)(=O)C=CN(C)C)cc3)nc(=O)c1-2
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred, solution of 23 mg (0.042 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of THF was added 1 mL of 2M diethylamine in THF. The solution was stirred 3 h and concentrated under reduced pressure. The product was dissolved in 1 mL of benzene and 0.05 mL of MeOH, frozen, and lyophilized to afford 25 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous white solid. 1H NMR (300 MHz, DMSO) δ 7.96(s, 2H); 7.19(d, 2H, J=8.5 Hz); 7.08(d, 2H, J=8.8 Hz); 3.79(s, 2H); 3.18-3.32(m, 1H); 3.13(t, 2H, J=7.5 Hz); 2.53(t, 2H, J=7.5 Hz); 1.99(s, 6H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1>CO.O1CCCC1.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc([N+](=O)[O-])c(N)nc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2cc(N)c(N)nc12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
0.4 g of palladium on active carbon (5% Pd) is added to a solution of 1.1 g of 2-amino-3-nitro-8-methylquinoline (compound B1) in 50 ml of methanol/tetrahydrofurane 1:1 and the resulting suspension is hydrated for 1 h. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is chromatographed on silica gel using dichloromethane/methanol 10:1 to give 0.79 g of the title compound as colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[N:9][NH:8][C:7]=3[C:11]([NH2:13])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[N:9][NH:8][C:7]=3[C:11]#[N:13]
Reactant: CC1(C)C2Cc3c(n[nH]c3C(N)=O)C21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C2Cc3c(n[nH]c3C#N)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide (0.532 g, 2.79 mmol) was taken up in THF (150 mL) and trifluoroacetic anhydride (0.936 g, 4.46 mmol) added. The resulting solution was stirred at room temperature under argon for 1 hour. Ethyl acetate (50 mL) was added and solvent removed under reduced pressure. The resulting pale yellow oil was taken up in DCM (100 mL), washed with saturated aqueous sodium bicarbonate solution (40 mL) and solvent removed under reduced pressure. The resulting white solid was taken up as a suspension in DCM (20 mL) and filtered to give (±)-1,1-dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile as an off-white solid. m/z (ES+): 174 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>CS(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
To a solution of 232 g of ethyl 4-hydroxybenzoate [XII; Alk=C2H5 ] in 1.2 liters of dimethylsulfoxide was added 100 g of potassium hydroxide. The mixture was stirred for five minutes, 678 g of 1,6-dibromohexane was then added, and the mixture stirred for four hours during which an exothermic reaction occurred (max. temp. 46° C.). The reaction mixture was added to 1500 ml of water and extracted three times with 800 ml of cyclohexane. The cyclohexane layer was washed with 800 ml of water, 200 ml 2N potassium hydroxide and 800 ml concentrated sodium chloride solution, then filtered and concentrated in vacuo. The residue was triturated with ether to give 328.1 g of ethyl 4-(6-bromohexyloxy)benzoate.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]=1O)([O-:3])=[O:2].[Cl:16]CCl>C1(P(Cl)(Cl)=O)C=CC=CC=1>[Cl:16][C:9]1[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=[C:5]([OH:15])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Reactant: ClCCl
Agent: O=P(Cl)(Cl)c1ccccc1
Product: O=[N+]([O-])c1c(Cl)cc(C(F)(F)F)nc1O
Temperature: 0 °C

Procedure:
3-Nitro-6-trifluoromethyl-pyridine-2,4-diol (5.8 gm, 26 mmol) was heated in phenylphosphonic dichloride (30 mL) at 100° C. for 19 hours. The resulting mixure was then cooled and poured on to ice (60 gm), and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (10% w/v) until the washings remained basic (pH ˜8). The deep yellow organic layer was then washed with saturated brine, dried over sodium sulphate, filtered and evaporated to give a yellow gum. Trituration of the gum with dichloromethane gave a yellow solid which was filtered off and dried (4.65 gm). The solid was dissolved in water (25 mL) and acidified with 2N hydrochloric acid (7.5 mL) to give a thick white precipitate which was filtered off and washed with water. The precipitate was dissolved in ethyl acetate, dried over sodium sulphate, filtered and evaporated to give the title compound as a white solid (3.75 gm).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9](=[O:42])[CH2:10][O:11][C:12]2[C:21]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:34]=[CH:33][N:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:31]=4)[CH2:24][CH2:23]3)=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[CH3:41])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[CH3:41][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:34]=[CH:33][N:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:31]=4)[CH2:24][CH2:23]3)[C:12]=1[O:11][CH2:10][C:9]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]1)=[O:42])[N:19]=[CH:18][CH:17]=[CH:16]2
Reactant: COC(=O)C1CN(C(=O)COc2c(C)cc3cccnc3c2N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2cccnc2c(N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)c1OCC(=O)N1CC(C(=O)O)C1
Yield: 67.6 %

Procedure:
1-(2-{6-Methyl-8-[4-(1-phenyl-1H-pyrazol-3-ylmethyl)-[1,4]diazepan-1-yl]-quinolin-7-yloxy}-acetyl)-azetidine-3-carboxylic acid methyl ester (70 mg, 0.12 mmol) was hydrolyzed with 2 N NaOH (0.15 mL) in THF (1 ml). After hydrolysis was complete, 2 N HCl (ca. 0.15 mL) was added to bring the pH to 7 and the mixture was extracted with 20% iPrOH in CH2Cl2 (3×10 mL). The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by reverse phase HPLC to afford the title compound (45 mg, 66%) as a light yellow solid. 1H NMR (400 MHz, DMSO) δ 8.75 (d, 1H, J=4.4 Hz), 8.42 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=1.6 and 8.4 Hz), 7.78 (d, 2H, J=8.0 Hz), 7.48-7.42 (m, 3H), 7.35 (q, 1H, J=4.4 Hz), 7.25 (t, 1H, J=7.2 Hz), 6.51 (d, 1H, J=2.8 Hz), 4.77 (s, 2H), 4.40 (t, 1H, J=10.0 Hz), 4.31 (t, 1H, J=6.4 Hz), 4.08 (t, 1H, J=9.2 Hz), 3.97-3.93 (m, 1H), 3.82 (s, 2H), 3.48-3.38 (m, 5H), 2.88 (s, 4H), 2.38 (s, 3H), 1.92 (m, 2H). MS (ES) m/z 555.5 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].CN([Si](C)(C)C)C(=O)C.CC([O:23][CH2:24][C:25]1[C:38]2[C:33](=CC=CC=2)[C:32](COC(C)=O)=[C:31]2[C:26]=1C=CC=C2)=O>ClCCl>[OH:4][CH2:3][CH:2]([NH:1][C:24](=[O:23])[C:25]1[CH:38]=[CH:33][CH:32]=[CH:31][CH:26]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: N[C@@H](CO)c1ccccc1
Agent: CC(=O)N(C)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC(CO)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A slurry of (R)-2-amino-2-phenylethanol (1.0 g, 7.4 mmol) in 50 mL dichloromethane was allowed to stir with N-methyl-N-(trimethylsilyl)acetamide (3.4 mL, 21.1 mmol) until a homogenous solution occured. The solution was cooled to 0° C. to 5° C. and a solution of 2,2'-dithiobis[benzoyl chloride] (1.0 g, 2.9 mmol) in 20 mL dichloromethane was added. The solution was stirred for 2 hours and 1 mL of 50% aqueous acetic was added causing the crude product to precipitate from solution. This solid was collected by filtration, washed with 1N HCl, water, and recrystallized from dimethylformamide/water to afford 1.2 g of the title compound, mp 235-236° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(OCCCCl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1ccc(OCCCCl)cc1
Yield: 36.6 %

Procedure:
To a solution of 4-(3-chloropropoxy)benzaldehyde (30 g) in methanol (250 mL), cooled at a temperature close to 0° C., is added portionwise sodium borohydride (7.72 g). The mixture is stirred for 4 hours, hydrolysed with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The combined extracts are dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel (eluent: dichloromethane/methanol from 100/0 to 95/5). Fractions containing the expected product are pooled and concentrated under reduced pressure to give 11.1 g of 4-(3-chloropropoxy)benzyl alcohol as a white solid used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[C:9]([C:11]([OH:13])=O)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].N1C2C=CC=C(O[P+](N(C)C)(N(C)C)N(C)C)C=2N=N1.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[C:9]([C:11]([NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[O:13])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2c(C(=O)O)cn3ncnc(N)c23)cc1F
Reactant: NCC(F)(F)F
Agent: CN(C)[P+](Oc1cccc2[nH]nnc12)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2c(C(=O)NCC(F)(F)F)cn3ncnc(N)c23)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
4-amino-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (24.6 g, 85.6 mmol) was added to a mixture of 2,2,2-trifluoro-1-aminoethane (42.4 g, 428 mmol), benzotriazolyloxytris(dimethylamino)phosphonium PF6 (56.8 g, 128 mmol) and 4-methylmorpholine (43.3 g, 428 mmol) in DMF (500 mL). The reaction mixture was stirred at rt for 16 h. The resulting precipitate was isolated by filtration and then washed with acetone and diethyl ether to give the desired product (22 g, 70%); 1H NMR (300 MHz, DMSO-d6) δ 8.37 (dd, J=8.5, 8.5 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.92-8.03 (br s, 1H), 7.89 (s, 1H), 6.99 (dd, J=12.2, 1.8 Hz, 1H), 6.85 (dd, J=12.2, 1.8 Hz, 1H), 6.74-6.6.82 (m, 1H), 5.35 (s, 2H), 5.13-3.22 (br s, 1H), 3.87-4.01 (m, 2H); ES-MS m/z 369.2 (MH)+; HPLC RT (Method B) 2.05 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[C:10]([O:14][C:15](OC([O-])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(#N)C.CN(C1C=CN=CC=1)C>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:2][CH2:3]1)(=[O:8])[NH2:9]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of piperidine-4-carboxamide (2 g, 15.6 mmol) in acetonitrile (30 mL), tert-butyldicarbonate (4.4 g, 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at r.t. overnight. It was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, brine and water. The organic phase was dried over Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to give 2.65 g (74%) of the title product.
Reaction SMILES: I.[CH3:2][N:3]([C:12]([S:14][CH3:15])=[NH:13])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16]([O:19][CH2:20][C:21](Cl)=[O:22])(=[O:18])[CH3:17]>C(=O)([O-])[O-].[K+].[K+].CC(C)=O>[C:16]([O:19][CH2:20][C:21]([N:13]=[C:12]([N:3]([CH3:2])[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[S:14][CH3:15])=[O:22])(=[O:18])[CH3:17]
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(=NC(=O)COC(C)=O)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Methyl 1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate, hydroiodide (1.34 g) was dissolved in saturated potassium carbonate solution and extracted with ether. The combined organic extracts were dried and evaporated to give an off-white solid which was dissolved in acetone (25 ml) and treated with potassium carbonate (1.1 g) followed by (acetyloxy)acetyl chloride (0.85 g). The suspension was stirred at room temperature for 2 h and evaporated in vacuo. The residue was suspended in water (50 ml) and filtered to give the title compound (1.01 g) which was recrystallised from ethanol, m.p. 115°-117°.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([S:10]([OH:13])(=O)=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.P(Cl)(Cl)([Cl:16])=O>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([S:10]([Cl:16])(=[O:13])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=S(=O)(O)c1cnc2ccccn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cnc2ccccn12
Temperature: 25 °C

Procedure:
The product from Step 1 (0.10 g, 0.5 mmol) was treated with phosphorus oxychloride (3 mL) and heated to reflux overnight. The reaction mixture was cooled to RT and treated with DCM (50 mL), poured into ice-water (100 mL), and then extracted with DCM (4×100 mL). The organic layers were combined and dried (Na2SO4), filtered, and concentrated to dryness under vacuum to give the title compound (0.10 g). 1H NMR (DMSO-d6) δ 8.87 (m, 1 H), 8.25 (s, 1 H), 7.98 (m, 2 H), 7.57 (m, 1 H).
Reaction SMILES: FC1C=C(C2C=CC=CC=2)C=CC=1C(=NO)CCC(O)=O.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[N:41][OH:42])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:31][C:30]=2[F:43])=[CH:25][CH:24]=1.ClC1C=CC(C2C=CC(C(=NO)CCC(O)=O)=C(F)C=2)=CC=1>>[F:43][C:30]1[CH:31]=[C:32]([C:35](=[N:41][OH:42])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:33]=[CH:34][C:29]=1[C:26]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)c(F)c1
Agent: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)cc1F
Agent: O=C(O)CCC(=NO)c1ccc(-c2ccccc2)cc1F
Product: O=C(O)CCC(=NO)c1ccc(-c2ccccc2)c(F)c1

Procedure:
4-(3-Fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; 4-(4′-Chloro-2-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid; and 4-(4′-Chloro-3-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][S:12][C:11](=[NH:10])[NH2:13])[CH:5]=1
Reactant: NC(N)=S
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1cccnc1
Temperature: 26 °C
Reaction time: 0.83 h
Yield: 72.1 %

Procedure:
A solution of 3-chloromethylpyridine hydrochloride (164 g) in ethanol (510 cc), at 50° C., is added dropwise and in the course of 20 minutes to a solution of thiourea (91 g) in boiling ethanol (510 cc). The reaction mixture is stirred for 3 hours 50 minutes at the boil and then cooled to 26° C. The resulting crystals are filtered off, washed twice with ethanol (400 cc in total) and dried under reduced pressure (25 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Pyrid-3-ylmethyl)-isothiourea dihydrochloride (173 g), melting at 212° C., is thus obtained.
Reaction SMILES: [C:1]([S:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:1]([S:9][CH2:10][C:11]([CH:17]1[CH2:18][C:19](=[O:20])[N:15]([OH:14])[C:16]1=[O:21])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CSC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(SCC(=O)C1CC(=O)N(O)C1=O)c1ccccc1
Temperature: 4 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
To a stirring solution of (9.20 g, 46.9 mmoles) benzoylmercaptoacetic acid and (5.41 g, 46.9 mmoles) N-hydroxysuccinimide in (100 mL) dioxane was added a solution of (9.70 g, 47 mmoles) dicyclohexylcarbodiimide in (40 mL) dioxane. The reaction was stirred 12 hours followed by cooling to 4° C., filtering, and rotavapping off the dioxane to a white solid. The solid was triturated with cold isopropanol, filtered, and dried in vacuo yielding 10.8 g, 78% benzoylmercaptoacetyl-N-hydroxysuccinimide. 200 mg was recrystallized from 500 mg in hot ethyl acetate.