Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 119 °C
Yield: 72 %

Procedure:
First, 9.00 g (107 mmol) of tiglic aldehyde and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.57 g (2.48 mmoles) of tributyl borate were added. Then the mixture was heated under reflux for 7 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 8.50 g of 2-benzenesulfonyl-5-methylpyridine as colorless crystals (purity of 99%, yield of 72% based on benzenesulfonyl cyanide).
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)C([O-])=O)=[O:4])[NH2:2].[CH:15]([O:20]C)([O:18][CH3:19])OC.O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:4]=[C:3]1[NH:1][N:2]=[CH:23][N:5]1[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:15]([O:18][CH3:19])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Reactant: NNC(=O)Nc1cc(C(=O)[O-])ccn1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccnc(-n2cn[nH]c2=O)c1
Temperature: 25 °C
Yield: 207.3 %

Procedure:
To a solution of 2-(hydrazinecarboxamido)isonicotinate (2.10 g, 10.0 mmol) in ethanol (140 mL) was added trimethyl orthoformate (2.43 g, 22.9 mmol) and p-toluenesulfonic acid monohydrate (0.70 g, 3.68 mmol) at ambient temperature. The reaction mixture was refluxed for 4 hours, cooled to ambient temperature and concentrated in vacuo to a minimum amount of volume. The solid was filtered, washed with cold methanol (20 mL) and dried in vacuo to give methyl 2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate as a colorless solid (1.68 g, 76%): MS (ES+) m/z 221.1 (M+1).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[C:31]#[CH:32])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>ClCCl.CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:33])[C:31]#[C:32][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([CH3:13])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: CC1CCN(Cc2ccc(I)cc2)CC1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)4-methylpiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 50 mg (27% of theory); C28H27ClN2O (M=442.99); calc.: molecular ion peak (M+H)+: 443/445; found: molecular ion peak (M+H)+: 443/445; Rf value: 0.45 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](F)=[C:11]([F:33])[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:13]([CH:24]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O>CN(C=O)C>[N:35]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][C:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:11]=1[F:33])=[N+:36]=[N-:37]
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of benzyl 5-benzyloxy-3,4-difluoro-2-((2-fluoro-phenyl)amino)benzoate (21.42 g, 46.22 mmol) in DMF (150 mL) was added NaN3 (3.61 g, 55.46 mmol). The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) and gave the desired product (pale yellow solid, 14.63 g, 65% yield). 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.49 (s, 1H), 7.39 (m, 10H), 7.07 (m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 6.83 (m, 1H), 5.31 (s, 2H), 5.13 (s, 2H).
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH:7]([C:17](Cl)=[O:18])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][CH2:23]O.C(N(CC)CC)C.[K+].[Br-].[OH2:34]>C1(C)C=CC=CC=1>[CH:1]1[C:12]2[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH:7]([C:17]([O:18][CH2:23][CH2:22][O:21][CH3:20])=[O:34])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COCCO
Reactant: O=C(Cl)C1Oc2ccccc2Cc2ccccc2O1
Reactant: O
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCOC(=O)C1Oc2ccccc2Cc2ccccc2O1
Temperature: 25 °C

Procedure:
12H-Dibenzo[d,g][1,3]dioxocin-6-carbonyl chloride (5.33 g, 19.5 mmol) is dissolved in toluene and added to a solution of 2-methoxyethanol (2.2 ml, 27.6 mmol) and 7 ml of triethylamine in toluene at 0°-10° C. under argon. The mixture is heated at reflux for 3 hours, cooled to room temperature, poured into 150 ml of water and extracted with 4×100 ml of ethyl acetate The resultant organic solution is washed with 5 percent hydrochloric acid, 5 percent sodium hydroxide and brine, dried with magnesium sulfate and filtered. The solvent is removed to give a brownish solid which is chromatographed on dry column silica gel, using ethyl ether/hexane (1:1) as the solvent, to give a yellowish oil. This oil is solidified, the solid is filtered and washed with ethyl ether/hexane to yield a white solid: mp 74°-76° C. IR (KBr) 1779, 1581 cm-1 ; 1H NMR (CDCl3) δ 3.42 (s, 3H, CH3), 3.3-4.0 (m, 3H, CH and OCH2), 4.35-4.8 (m, 3H, CH and OCH2), 5.1 (s, 1H, OCHO), 6.9-7.45 (m, 8H, aromatic).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12](S(C)=O)[N:11]=[C:10]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)[CH:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C)C(=O)C>O>[F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:11]=[C:10]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)[CH:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1
Reactant: CS(=O)c1nc(OCC2CCN(NC(=O)OC(C)(C)C)CC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NN1CCC(COc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfinyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (240 mg), morpholine (0.3 mL), and N,N-dimethylacetamide (2 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-50:50) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (246 mg) as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C@H:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9][C@@H:10]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:8])[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[Cl:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>CC#N>[Cl-:29].[S:1]1[CH:5]=[C:4]([C@H:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9][C@@H:10]2[CH:15]3[CH2:16][CH2:17][N+:12]([CH2:30][C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([CH2:13][CH2:14]3)[CH2:11]2)=[O:8])[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@@H](Nc1ccccc1)c1csc2ccccc12
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@@H](Nc1ccccc1)c1csc3ccccc13)C2)c1ccccc1
Product: [Cl-]
Yield: 31.8 %

Procedure:
A solution of (S)—((R)-quinuclidin-3-yl) 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (diastereomer 2 of C19) (230 mg, 0.586 mmol) and 2-chloro-1-phenylethanone (91 mg, 0.586 mmol) in dry CH3CN (2 ml) was stirred at r.t. for 24 hours. Then the solvent was evaporated and the residue was purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (R)-3-((S)-2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (102 mg, 31.8% yield).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1C=CC=CC=1>[C:22]1([O:21][C:19]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C#N)=NO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=NOC(=O)Oc1ccccc1
Temperature: 0 °C
Yield: 124.8 %

Procedure:
In dry benzene (50 ml), ethyl 2-hydroxyimino-2-cyanoacetate (7.1 g) and triethylamine (7.0 ml) are dissolved, and the obtained solution is cooled with ice-water. A solution of phenyl chloroformate (7.8 g) in dry benzene (50 ml) is dropwise added thereto while stirring, and the resulting mixture is stirred for 1 hour and allowed to stand over night. The reaction mixture is filtered, and the filtrate is washed with water, dried and concentrated to give ethyl 2-phenyloxycarbonyloxyimino-2-cyanoacetate (16.3 g) as an oil.
Reaction SMILES: N1C2C(=C(C3N=[C:12]([N:22]4[CH2:27]COCC4)[C:13]4S[C:17](COC)=[CH:16][C:14]=4N=3)C=CC=2)C=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.N1C=CC=C(CCl)C=1>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:17][C:16]3[CH:27]=[N:22][CH:12]=[CH:13][CH:14]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3cccnc3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with 3-picolyl chloride to give 4-(2-chloro-6-((pyridin-3-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine. Suzuki coupling of 4-(2-chloro-6-((pyridin-3-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 7 was carried out via General Procedure A. Purification using column chromatography gave 319. NMR: CDCl3: 3.90-3.94 (4 H, m, CH2), 4.08-4.13 (4 H, m, CH2), 4.68 (2 H, s, CH2), 4.88 (2 H, s, CH2), 7.30 (1 H, dd, J 7.79 and 4.87, Ar), 7.44 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.57 (1 H, d, J 8.20, Ar), 7.71 (1 H, d, J 7.79, Ar), 8.28 (1 H, d, J 7.35, Ar), 8.58 (1 H, dd, J 4.80 and 1.47, Ar), 8.63 (1 H, d, J 1.86, Ar) and 9.02 (1 H, s, Ar). MS: (ESI+): MH+ 459.16
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[Cl:19]>>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[C:13]([Cl:19])[CH:14]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: Nc1ncnc(Cl)c1C=O
Product: Nc1ccc(Oc2ncnc(N)c2C=O)cc1Cl

Procedure:
Using the procedure for Example 1, 4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1a was reacted with 4-amino-3-chloro-phenol Compound 10a to provide 4-amino-6-(4-amino-3-chloro-phenoxy)-pyrimidine-5-carbaldehyde Compound 26a.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:27][CH2:26][C@:25]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[H-].[Na+].Br[CH2:36][C:37]([O:39]CC)=O.CO.[NH3:44]>CN(C=O)C>[CH2:1]([C@:3]12[CH2:27][CH2:26][C@@:25]([O:28][CH2:36][C:37]([NH2:44])=[O:39])([C:29]([F:32])([F:31])[F:30])[CH2:24][C@@H:4]1[CH2:5][CH2:6][CH2:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)CBr
Reactant: CC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC[C@]12CC[C@@](OCC(N)=O)(C(F)(F)F)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 0 °C
Yield: 18 %

Procedure:
A flask with stir bar and nitrogen line was charged with (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.230 g, 0.515 mmol)], DMF (3 mL) and sodium hydride (60 wt % in oil, 12.0 mg, 0.30 mmol). The mixture was stirred at rt for about 20 min then cooled to about 0° C. Ethyl 2-bromoacetate (0.086 g, 0.515 mmol) was added then the mixture was allowed to warm to rt for about 12 h. Sodium hydride (60 wt % in oil, 20 mg, 0.500 mmol) was added then after about 15 min ethyl 2-bromoacetate (0.120 g, 0.719 mmol) was added dropwise over about 1 h. Sodium hydride (60 wt % in oil, 20 mg, 0.50 mmol) was added then after about 10 min ethyl 2-bromoacetate (0.120 g, 0.719 mmol) was added dropwise over about 10 min. The mixture was concentrated under reduced pressure, dissolved in 7 M ammonia in MeOH (5 mL, 35.0 mmol) transferred to a microwave vial and heated in a microwave at about 130° C. for about 1 h. The reaction mixture was purified without manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 um particle size) with a gradient of 15-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then lyophilized to yield 2-(((3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-yl)oxy)acetamide (0.046 g, 18%); LC/MS, method 2, Rt=2.82 min, MS m/z 504 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.7 Hz, 1H), 7.84 (s, 1H), 7.83-7.77 (m, 2H), 7.57 (s, 1H), 7.45-7.37 (m, 2H), 7.33 (s, 1H), 7.20 (s, 1H), 4.02 (d, J=14.7 Hz, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.27-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.26-1.97 (m, 5H), 1.94-1.80 (m, 4H), 1.79-1.56 (m, 3H), 1.40-1.30 (m, 1H), 0.44 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([N:13]=[C:14]=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2.C(OCC)(=[O:28])C>>[N:17]12[CH2:18][CH:19]([CH2:21][CH2:22]1)[C@H:20]([O:15][C:14](=[O:28])[NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:23][CH2:24]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(C)=O
Reactant: O=C=Nc1ccccc1-c1ccccc1
Agent: Cl
Product: O=C(Nc1ccccc1-c1ccccc1)O[C@@H]1CCN2CCC1C2
Yield: 99 %

Procedure:
2-Biphenyl isocyanate (1.00 g, 5.12 mmol) and (R)-(−)-3-quinuclidinol hydrochloride (921 mg, 5.63 mmol) were heated together in N,N-dimethylformnamide (2.06 mL) at 110° C. for 12 h. The reaction mixture was cooled and diluted with ethyl acetate (15 mL) and then washed with saturated aqueous sodium bicarbonate (2×10 mL). The organic layer was extracted with 1 M hydrochloric acid (3×20 mL) and the combined aqueous extracts were made basic to pH 8-9 with potassium carbonate. The aqueous layer was then extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried (magnesium sulfate) and solvent was removed under reduced pressure to give the title compound as a yellow oil (1.64 g, 99% yield).
Reaction SMILES: C([O-])C.Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.[CH3:30][N:31]=[C:32]=[O:33]>ClCCl>[CH3:30][NH:31][C:32]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:33]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN=C=O
Agent: CC[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a solution of 2.0 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride monoethanolate and 5.0 mL (36 mMol) triethylamine in 100 mL dichloromethane were added 0.74 mL (12.6 mMol) methyl isocyanate. The reaction mixture was stirred for 15 minutes and was then washed with 100 mL of water. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was crystallized from acetonitrile to give 1.05 gm (64%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22]Br>CN(C)C=O>[C:1]([O:5][C:6](=[O:9])[N:7]([CH2:22][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Reactant: CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1c(Br)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of methyl-carbamic acid tert-butyl ester from Preparation 1 (5.347 g, 40.76 mmol) in 200 ml anhydrous dimethylformamide was added sodium hydride (2 g of a 60% suspension in mineral oil, 50 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 30 minutes, at which time the initial off-gassing had completed. 1-bromo-2-bromomethyl-3-nitro-benzene (12 g, 40.7 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extract with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give (2-bromo-6-nitro-benzyl)-methyl-carbamic acid tert-butyl ester as a yellow oil (11.761 g, 84%). MS: (M+H)+ 345.1.
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH:11](CC2C=CC=CC=2)[OH:12])[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12>[Pd].CO.C(O)(=O)C>[C:4]1(=[O:20])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:1](=[O:25])[C:2]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCNCCC(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCNCCCO
Reaction time: 3 h
Yield: 84.6 %

Procedure:
N-Phthalimidoethyl(benzyl)-3-amino-1-propanol (4.62 g, 11.95 mmol), Pd/C 10% (1 g) and MeOH:acetic acid (95:5, v/v) (100 mL) was transferred to a 250 mL par hydrogenation flask. The flask was purged and filled with H2 three times and then left under H2 at 55 psi with shaking. The mixture absorbed 20 psi of H2 in 30 minutes. The shaking was stopped and the pressure was raised to 55 psi again. After 3 hrs the pressure was 45 psi so the pressure was increased to 55 psi once more. The reaction was complete as indicated by TLC dichloromethane:MeOH (9:1, v/v) in 4 hours. The reaction mixture was filtered though a bed of celite and the solvent evaporated under vacuo to leave a yellowish oil. The oil was purified by silica gel flash column chromatography using dichloromethane:MeOH (9:1, v/v) as the eluent. The appropriate fractions were combined and concentrated under vacuo to afford 2.51 g (68%) of the title compound as a white solid (rn.p. 94-95° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:24][CH2:25][CH3:26])[C:13](I)=[C:14]([O:16][S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH:15]=2)=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([NH:34]C(=O)C(F)(F)F)=[C:30]([CH3:41])[CH:29]=1.C(O)C>O1CCOCC1.C(COC)OC>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:13]2[C:12]([O:24][CH2:25][CH3:26])=[CH:11][C:10]([CH2:9][C:5]3[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:15][C:14]=2[O:16][S:17]([CH:20]2[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:29][C:30]=1[CH3:41]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1I
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Solvent: COCCOC
Solvent: C1COCCO1
Solvent: CCO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C2CC2)c1-c1ccc(N)c(C)c1
Yield: 30 %

Procedure:
Starting from cyclopropanesulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester (294 mg; 0.6 mmol) and N-(4-bromo-2-methyl-phenyl)-2,2,2-trifluoroacetamide (282 mg; 1.0 mmol) (first step in 12 ml dioxane instead of dimethylformamide with bis-triphenylphosphine-palladium dichloride (56 mg; 0.08 mmol) and second step in dimethoxyethane (8 ml) and ethanol (2 ml) with tetrakis-triphenylphosphine-palladium (69 mg; 0.06 mmol)), 151 mg (30%) cyclopropanesulphonic acid 4′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-methyl-biphenyl-2-yl ester are obtained as a colourless powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:19]([OH:21])[N:17]=[C:15]([OH:16])[C:3]=3[N:4]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Oc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1

Procedure:
A solution of 3-amino-6-(4-fluorophenyl)picolinamide (2.48 g) and triphosgene in 1,4-dioxane (50 mL) was heated to 100° C. for 1 hour. Cooling and filtration provided 2.2 g of 6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine-2,4-diol which was characterized by its mass spectrum as follows: MS (m/z) 258 [M+H]+.
Reaction SMILES: C[CH:2]([C:4]1C=CC=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[S:49]1C=CC(CC(O)=O)=C1>>[S:49]1[CH:2]=[CH:4][C:5]([CH2:13][C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])=[CH:6]1
Reactant: O=C(O)Cc1ccsc1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2ccsc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 3-thiopheneacetic acid, mp 136°-138° C.