Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH2:16])=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl.C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH:16][C:29](=[O:31])[CH3:30])=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCn1c(=O)c2[nH]c(N)nc2n(CCCC)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)c2[nH]c(NC(C)=O)nc2n(CCCC)c1=O

Procedure:
1.3-Di-n-butyl-8-amino xanthine (0.5 g), hydrochloride in toluene (30 ml) was stirred for 30 minutes with triethylamine (0.16 g). After addition of acetic anhydride (0.32 g), the mixture was refluxed for 6 hours. The reaction mixture was extracted with water (4×30 ml), the organic layer separated and dried over anhydrous sodium sulphate. The solvent was then evaporated to yield the product, yield 0.1 g (20%), mpt. 180° C.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])C.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25]([NH2:27])=[NH:26]>>[CH2:13]([N:8]1[CH2:9][CH2:10][C:11]2[N:27]=[C:25]([C:24]3[CH:28]=[C:29]([Cl:31])[CH:30]=[C:22]([Cl:21])[CH:23]=3)[N:26]=[C:4]([OH:5])[C:6]=2[CH2:7]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N=C(N)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2

Procedure:
The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3,5-dichloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.70-2.90 (m, 4H), 3.20-3.50 (m, 4H), 3.70-3.90 (m, 2H), 7.10-7.50 (m, 6H), 7.83 (s, 1H), 8.12 (s, 2H), 12.70 (br s, 1H); MS: m/z (ESI) 386 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[C:4]([O:17][CH3:18])[CH:3]=1.[Mg].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:17][CH3:18])[CH:3]=2)([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cc(Br)ccc1N1[Si](C)(C)CC[Si]1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Bromo-2-methoxy-phenyl)-2,2,5,5-tetramethyl-[1,2,5]azadisilolidine (250 mg, 1.0 equiv) was dissolved in anhydrous THF (4 ml) under an argon atmosphere. A 1M suspension of magnesium in THF (0.941 ml, 1.33 equiv) was added dropwise at room temperature, and the mixture was stirred for 2 hours. It was then transferred via cannula to a room temperature solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (145 mg, 1.0 equiv), and the mixture was heated to reflux 2 hours. Cooled to room temperature and quenched with water. Partitioned between EtOAc/water. Dried over sodium sulfate and concentrated. Purified by preparative TLC, 40% EtOAc/hexane. Obtained 4-(4-amino-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a purple foam, 52 mg. LCMS (E/I+) 323 (M+H). NMR 1H (CDCl3) 6.95 (s, 1H), 6.83 (d, J=5.82 Hz, 1H), 6.62 (d, J=5.73 Hz, 1H), 3.92-4.05 (m, 2H), 3.88 (s, 3H), 3.17-3.30 (m, 2H), 1.89-2.10 (m, 2H), 1.68-1.74 (m, 2H), 1.46 (s, 9H), 1.23 (s, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[C:17]([C:36]2[CH:48]=[C:47]([F:49])[C:39]3[N:40]=[C:41]([CH3:46])[N:42]([CH:43]([CH3:45])[CH3:44])[C:38]=3[CH:37]=2)=[N:18][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:25][N:24]=2)=[N:20][CH:21]=1.[CH3:50][C:51]([CH3:53])=O.ClCCCl>C(O)(=O)C>[F:15][C:16]1[C:17]([C:36]2[CH:48]=[C:47]([F:49])[C:39]3[N:40]=[C:41]([CH3:46])[N:42]([CH:43]([CH3:45])[CH3:44])[C:38]=3[CH:37]=2)=[N:18][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH:51]([CH3:53])[CH3:50])[CH2:34][CH2:35]3)=[CH:25][N:24]=2)=[N:20][CH:21]=1
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCNCC5)cn4)ncc3F)cc2n1C(C)C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCN(C(C)C)CC5)cn4)ncc3F)cc2n1C(C)C
Temperature: 60 °C

Procedure:
Add sodium triacetoxyborohydride (299.9 mg) to a mixture of [5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-(5-piperazin-1-ylmethyl-pyridin-2-yl)-amine (130 mg), acetone (31.6 μL), 1,2-dichloroethane (9 mL) and acetic acid (16.3 μL). Heat at 60° C. for 1 h. Remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2 M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2 M (3%) to afford 115 mg of the title compound. MS (ES+): m/z=521 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:4].[CH3:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>>[CH2:15]([O:14][C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:17][C:18]([N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:3](=[O:4])[CH2:2][NH:1][C:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=1)=[O:37])=[O:13])[CH3:16]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN
Product: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 52.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(2-ethoxycarbonylphenyl)acetamido]-N-methyl-N-phenylacetamide (2.25 g) and 3-methylphenyl isocyanate (0.88 g), and after recrystallisation in ethyl acetate, 2-{N-(2-ethoxycarbonylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (1.6 g), m.p. 201° C., is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])[NH:7][CH:8]=1.C(Cl)Cl.[OH-].[NH4+:21]>>[CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]([NH2:21])=[O:12])[NH:7][CH:8]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)Cc1c[nH]c(CCC(=O)Cl)n1
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C)(C)Cc1c[nH]c(CCC(N)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanoyl chloride in methylene chloride (0.3 M) (7.8 mL, 2.3 mmol) was added to a rapidly stirred solution of concentrated aqueous ammonium hydroxide (2.5 mL) at 0° C. After stirring at rt for 1 h, the volatiles were removed to afford the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH:40][CH3:41]>C(Cl)Cl>[CH3:39][N:40]([CH3:41])[C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 6, 0.1 g, 0.196 mmol) in DCM (2 mL) was added oxalyl chloride (0.023 g, 0.193 mmol) at 0° C. Reaction mixture was stirred at room temperature for 1 hour and cooled to 0° C. followed by addition of dimethyl amine (gas) was purged for 2 hours. Resulting reaction mixture was stirred at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was diluted with DCM (3 mL), washed with water (3×3 mL). Organic layer was dried over sodium sulphate and evaporated in vacuo to get crude thick oil (0.077 g). Crude was purified by column chromatography on silica gel (100-200 mesh size), compound was eluted using 2% methanol in DCM and crystallized with chloroform:pentane (1:9) to afford off white solid (0.035 g, 33%). 1H-NMR (400 MHz, CDCl3) δ: 2.79-2.80 (m, 1H), 2.80-2.94 (m, 4H), 2.97 (s, 3H), 2.99 (s, 3H), 3.66-3.69 (m, 1H), 4.07 (d, 1H, J=17.16 Hz), 7.51 (d, 2H, J=8.16 Hz), 7.63-7.65 (m, 4H); LC-MS (m/z): [M−H] 535.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Reactant: Oc1ccc(OCCN2CCCCCC2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Yield: 42.4 %

Procedure:
Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol), potassium carbonate (25 g, 181 mmol) and pyridine (400 mL). Heat the reaction mixture to reflux for 85 hours. Cool and filter the residue with celite and elute with methanol and methylene chloride (500 mL, V/V=1:5). Evaporate solvent under reduced pressure and chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane. Dissolve 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 mL). Heat the mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate (30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30 minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7 mmol). Heat to reflux for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g (97%) of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:51]4[C:56]([CH3:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=4[CH3:59])=[C:16]4[N:50]=[C:19]([C:20]([C:41]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=5[CH3:49])=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[CH3:60][O:61][P:62]([O:65]C)[O:63][CH3:64]>C1(C)C=CC=CC=1>[CH3:60][O:61][P:62]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:51]4[C:56]([CH3:57])=[CH:55][C:54]([CH3:58])=[CH:53][C:52]=4[CH3:59])=[C:16]4[N:50]=[C:19]([C:20]([C:41]5[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=5[CH3:49])=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1)([O:63][CH3:64])=[O:65]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(CBr)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5c(C)cc(C)cc5C)c5ccc2[nH]5)C=C4)C=C3)cc1)OC
Yield: 79 %

Procedure:
A solution of 26 (200 mg, 240 μmol) in trimethylphosphite (2.2 mL) and toluene (5 mL) was heated to 120° C. under argon for 17 h. The reaction mixture was cooled and concentrated under vacuum. The residue was chromatographed [silica, CHCl3→CHCl3/ethyl acetate (95:5)] to afford a purple solid (164 mg, 79%): 1H NMR δ −2.57 (br s, 2H), 1.84-1.85 (m, 18H), 2.62 (s, 9H), 3.50 (d, J=21.6 Hz, 2H), 3.87 (d, J=1.1 Hz, 6H), 7.27 (s, 6H), 7.67 (dd, J1=8.4 Hz, J2=1.8 Hz, 2H), 8.15 (d, J=7.8 Hz, 2H), 8.63 (s, 4H), 8.67 (d, J=4.8 Hz, 2H), 8.75 (d, J=4.8 Hz, 2H); 31P NMR δ 29.50; LDMS obsd 863.2; FABMS obsd 862.4045; calcd 862.4012 (C56H55N4O3P); λabs=421, 514, 547, 593, 649 nm.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18]
Reactant: ClCCCCBr
Reactant: O=c1ccc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2n1CCCCCl

Procedure:
0.30 g of sodium hydride (60% oily) was added to a dimethylformamide (20 ml) solution of 1.0 g of 1H-quinolin-2-one while being stirred under ice-cooling and stirred at room temperature for 0.5 hour, and after that 1.6 ml of 1-bromo-4-chlorobutane was added and stirred at room temperature for 14 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and 1.02 g of 1-(4-chlorobutyl)-1H-quinolin-2-one was obtained in the form of colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[N+:15]([C:18]1[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]([OH:28])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C=O)C.O>[CH2:2]([O:28][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cccnc12
Temperature: 90 °C
Yield: 68.5 %

Procedure:
Bromomethyl-benzene (424 μl, 3.57 mmol) and K2CO3 (493 mg, 3.57 mmol) were added to a solution of 8-nitro-quinolin-5-ol 563 (566 mg, 2.98 mmol) in DMF (5 ml) and the mixture was heated at 90° C. for 6 h. After cooling, the mixture was diluted with water (25 ml) and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound (572 mg, 69%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:16][CH:15]([C:17]([O:19]C)=[O:18])[NH:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:16][CH:15]([C:17]([OH:19])=[O:18])[NH:14][CH2:13][CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:26])([F:28])[F:27])[N:3]=1
Reactant: COC(=O)C1CC2(CCN1)CCN(c1cc(O[C@H](c3ccc(Cl)cc3-n3ccc(C)n3)C(F)(F)F)nc(N)n1)CC2
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CCNC(C(=O)O)C4)CC3)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of methyl 9-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate using the LiOH general method provides the title compound as an off-white solid.
Reaction SMILES: O=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.Cl>S(=O)(=O)(O)O.O>[C:9]1([C:8]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:21][C:2]=2[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A mixture of Example 1A (7.81 g, 40.7 mmol) and phenylhydrazine (4.00 mL, 40.7 mmol) was treated with concentrated sulfuric acid (4 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (50 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (100 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 3.43 g (32%) of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14].[CH3:16][O-:17].[Na+]>CO>[F:14][C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([O:17][CH3:16])=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of methyl-2,5-difluoro-4-nitrobenzoate (1 g, 4.6 mmol) in methanol (10 mL) was added sodium methoxide (95%, 393 mg, 6.9 mmol). The reaction mixture was stirred at room temperature overnight. It was then concentrated, acidified with HCl. Solid was filtered and dried to give the product as light yellow powder (728 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H) 7.66 (d, J=4 Hz, 1H) 8.01 (d, J=8 Hz, 1H).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2S(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[CH3:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: COCc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Product: COCc1cccc2[nH]ccc12
Temperature: 0 °C
Yield: 77.9 %

Procedure:
A solution of 2.84 g of sodium in 155 ml of ethanol is dripped within 10 minutes into a solution of 15.57 g of 4-methoxymethyl-1-tosylindole in 155 ml of ethanol, whereupon the mixture is heated with reflux for 11/2 h; next it is cooled, stirred into 1.5 liters of half-saturated ice-cold sodium-di-hydrogen-phosphate solution, extracted with ethyl acetate; whereupon, the ethyl-acetate extracts are washed neutral with water. After the solvent has been distilled off, the raw product is chromatographed on silical gel with hexane/ethyl-acetate (0-20%). 6.2 g of 4-methoxymethyl-indole is obtained in the form of a colorless oil.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)[CH3:5].C(O)C>[C].[Pd].O>[ClH:1].[ClH:1].[CH3:3][N:4]([CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:5]
Reactant: CN(C)CC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)CC1CNCCO1

Procedure:
A mixture of 22.5 g of 4-benzyl-2-chloromethylmorpholine, 200 ml of ethanol and 200 ml of an aqueouos 26,7% dimethylamine solution is heated at 150° C. for 5 hours in an autoclave. After completion of the reaction, the solvent is distilled off under reduced pressure. After adding water, the residue is extracted with toluene three times. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is treated with 37% hydrochloric acid-ethanol to give 2-(N,N-dimethylaminomethyl)-4-benzylmorpholine dihydrochloride as white crystals. A mixture of 22.9 g of the hydrochloride compound, 200 ml of ethanol and 100 ml of water is subjected to catalytic reduction with 2.3 g of 10% palladium-carbon at ordinary temperature and atmospheric pressure. After absorbing a theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol to give 2-(N,N-dimethylaminomethyl)morpholine dihydrochloride as white crystals, melting at 270°-271° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.O>[F:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)ncc(OC)c2c1
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(F)ncc(OC)c2c1
Temperature: 145 °C
Yield: 20.1 %

Procedure:
To a solution of 1-chloro-4,6-dimethoxyisoquinoline (1.5 g, 6.71 mmol) in DMSO (15 ml) was added cesium fluoride (4 g, 26.8 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (280 mg, 20.15%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.99-7.97 (d, J=8 Hz, 1H), 7.44-7.39 (m, 2H), 7.27-7.11 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H); 19F NMR: δ ppm −79.32 (1 F); MS: MS m/z 208.0 (M++1).
Reaction SMILES: O[CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH3:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:32][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCN
Product: CCCCCCCCNC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
The process was carried out in essentially the same manner as in Examples 5 and 6 above, using 21 g of lactose and 12.8 g of octylamine.
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=CC=[CH:3][CH:2]=1.[CH3:12][O:13]CC1(O)CC1>>[CH3:12][O:13][CH2:6][C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH2:3][CH2:2]1
Reactant: COCC1(O)CC1
Reactant: NS(=O)(=O)Oc1ccccc1
Product: COCC1(OS(N)(=O)=O)CC1

Procedure:
Sulfamic acid 1-methoxymethyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-methoxymethyl cyclopropanol (synthesized by methods reported in European Journal of Chemistry 2006, 5069) to obtain sulfamic acid 1-methoxymethyl-cyclopropyl ester.