Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]1([C:18]2[C:27]([CH:28]([OH:39])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[C:26]([CH:40]([CH3:42])[CH3:41])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:45])[CH2:21][C:22]([CH3:44])([CH3:43])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.CO>O1CCCC1>[C:12]1([C:18]2[C:27]([C@H:28]([OH:39])[C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[C:26]([CH:40]([CH3:41])[CH3:42])[CH:25]=[C:24]3[C:19]=2[C@@H:20]([OH:45])[CH2:21][C:22]([CH3:43])([CH3:44])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
230 μl (1.27 mmol) of borane/N,N-diethylaniline complex are added very slowly to a solution of 7.10 mg (50 μmol) of (1R,2S)-1-aminoindan-2-ol in 7.5 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 150 mg (320 μmol) of 5-cyclohex-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 35A) in 7.5 ml of tetrahydrofuran are then added very slowly dropwise over a period of 30 min. The mixture is stirred overnight, methanol is then added and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→1:1) and subsequent preparative HPLC (method 1) gives the diastereomerically pure target compounds, which for their part are present as a mixture of two rotamers.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>C(#N)C.CCOC(C)=O>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([C:1]#[C:2][CH2:3][CH3:4])[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#CCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
But-1-yne (g) was during 5 min gently bubbled through anhydrous acetonitrile cooled in an ice-water bath. The resulting solution contained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57 mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were added sequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol), bis(triphenylphosphine)-palladium(IT) chloride (0.458 g, 0.65 mmol) and CuT (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc and passed through a short plug of silica. The solvents were evaporated and the residue was purified by flash chromatography on silica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of the title compound (87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 4 H), 2.47 (q, 3 H), 8.11 (t, 1 H), 8.57 (d, 1 H), 8.65 (d, 1 H); MS (ES+) m/z 210 [M+H]F.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[NH:12]([C:16]1[O:20][N:19]=[C:18]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:17]=1)[C:13]([NH2:15])=[NH:14].[NH3:26]>>[NH2:26][C:7]1[C:3]([NH:25][CH2:24][CH2:23][S:22][CH2:21][C:18]2[N:17]=[C:16]([NH:12][C:13]([NH2:15])=[NH:14])[O:20][N:19]=2)=[N:4][S:5](=[O:10])(=[O:11])[N:6]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: N
Reactant: N=C(N)Nc1nc(CSCCN)no1
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2N)no1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamine and excess ammonia, the title compound is thereby produced.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][Br:1])([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
α-Bromo-p-toluic acid (21.5 g, 100 mmol) was added in five equal portions to 90% HNO3 (250 mL) at −10° C. The reaction mixtures were stirred at −10° C. for 3 h and poured into ice-water. After stirring at room temperature for 3 h, the white precipitate was filtered, collected and dried by air overnight to give ortho-nitro α-bromo-p-toluic acid (22.2 g, 85%) as slightly yellow solid.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([CH2:35][C:36]([NH:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42])=[S:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>N1C=CC=CC=1>[CH2:21]([CH2:35][C:36]([NH:38][CH2:39][CH:40]([OH:43])[CH2:41][O:42][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[S:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=S)NCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=S)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Chlorotriphenylmethane (2.833 g, 10.16 mmol) was added to a solution of 3-tetradecylthioacetylaminopropane-1,2-diol (example 2) (3 g, 8.30 mmol) in pyridine (2.5 ml). The reaction mixture was stirred at 50° C. for 24 hours and the solvent was then vacuum evaporated. The residue was taken up in water and extracted with dichloromethane. The organic phase was washed with 1 N aqueous hydrochloric acid then with an aqueous solution saturated in sodium chloride. It was dried on magnesium sulfate, filtered and the solvent was evaporated. The residue obtained (6.36 g) was purified by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 98:2) to give the desired compound in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN1CCCC1=O>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[S:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1ncsc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ncsc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 79.1 %

Procedure:
Using 4-methyl-1,3-thiazole-5-carboxylic acid (143 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (179 mg, yield 79%) was obtained.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:42]([O-:46])([O-])(=[O:44])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:42]([C:15]1[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:35])([F:36])[C:31]([F:32])([F:34])[F:33])=[CH:26][N:25]=2)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:46])=[O:44])[CH3:3]
Reactant: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(C(F)(F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.25 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.18 g of 3-ethylsulfanyl-N-(5-pentafluoroethylpyridin-2-yl)picolinamide (Compound of Present Invention 46) and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.15 g of 3-ethylsulfonyl-N-(5-pentafluoroethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 47).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15]N(C)CCN(C)C.C([Li])(CC)C.CI>C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCCCOc1ccc(C(=O)O)c(C)c1
Temperature: -90 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-butoxybenzoic acid (10 g), N,N,N′,N′-tetramethylethylenediamine (13.2 g) and THF (75 mL) was cooled to −90° C., and sec-butyllithium (81 mL; 1.4 M in hexane) was added over the course of 30 minutes. After a further 30 minutes, the mixture was warmed to −78° C., and a solution of methyl iodide (12.8 mL) in THF (10 mL) was added dropwise. The reaction solution was allowed to warm to room temperature and the mixture was hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product with the molecular weight of 208.26 (C12H16O3) was obtained in this way; MS (ESI): 209 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccc(F)cc1
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: COCCOC
Product: Fc1ccc(-c2ccc(Br)cn2)cc1
Yield: 88.4 %

Procedure:
To a degassed mixture of 2,5-dibromopyridine (500 mg, 2.11 mmol) and 4-fluorobenzeneboronic acid (444 mg, 3.17 mmol) in ethylene glycol dimethyl ether (4.2 ml) and 2M aqueous sodium carbonate (2.1 ml) was added tetrakis(triphenylphosphine)palladium(0) (98 mg, 0.08 mmol). This mixture was heated at reflux for 14 h. After cooling the crude reaction was partitioned between water and dichloromethane. The organics were dried over anhydrous magnesium sulfate, filtered and adsorbed onto silica. Purification by chromatography on silica gel, eluting with a mixture of 4% diethyl ether in isohexane, gave 5-bromo-2-(4-fluorophenyl)pyridine (470 mg) as a white solid: δH (360 MHz, CDCl3) 7.30 (1H, d, J 7), 7.12-7.19 (2H, m), 7.57 (1H, d, J 8), 7.86 (1H, dd, J 2 and 8), 7.92-7.98 (2H, m), 8.72 (1H, d, J 2), m/z (ES+) 251, 252, 253, 254 (M++H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=1[N:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=3[N:52]([CH3:54])[CH3:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CN(C)c1c(Cl)cncc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CN(C)c1c(Cl)cncc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-5-chloro-N,N-dimethylpyridin-4-amine hydrobromide and isolated as light-yellow gum. MS (m/e): 451.4 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[C:34]2[C:29](=[CH:30][C:31]([CH2:35][N:36]3[C:44]4[C:39](=[N:40][CH:41]=[C:42]([C:45]5[CH:53]=[CH:52][C:48]([C:49]([OH:51])=O)=[CH:47][CH:46]=5)[N:43]=4)[N:38]=[N:37]3)=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[CH3:54][N:55]([CH3:60])[CH2:56][CH2:57][NH:58][CH3:59].C(N(CC)CC)C>CN(C=O)C>[CH3:54][N:55]([CH3:60])[CH2:56][CH2:57][N:58]([CH3:59])[C:49](=[O:51])[C:48]1[CH:47]=[CH:46][C:45]([C:42]2[N:43]=[C:44]3[N:36]([CH2:35][C:31]4[CH:30]=[C:29]5[C:34](=[CH:33][CH:32]=4)[N:25]=[CH:26][CH:27]=[CH:28]5)[N:37]=[N:38][C:39]3=[N:40][CH:41]=2)=[CH:53][CH:52]=1
Reactant: CNCCN(C)C
Reactant: O=C(O)c1ccc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCN(C)C(=O)c1ccc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 18 h
Yield: 57.9 %

Procedure:
HATU (82 mg, 0.22 mmol) was added to a mixture of 4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzoic acid (75 mg, 0.20 mmol), N1,N1,N2-trimethylethane-1,2-diamine (22 mg, 0.22 mmol) and triethylamine (0.060 mL, 0.43 mmol) in DMF (2.0 mL). After stirring for 18 hours, the reaction was partitioned between dichloromethane:ethanol (9:1) and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 108 mg of crude material. The material was purified by pre-HPLC to give N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzamide (54 mg, yield 48%).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].C1(C)C=CC=CC=1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:3][C:1]([O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2]
Reactant: Oc1cccnc1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)Oc1cccnc1

Procedure:
A 1.93M solution of phosgene in toluene (20%) (198.3 ml) (382.3 mmoles) was diluted with dry CH2Cl2 (100 ml) and the mixture was stirred at 0° under an argon atmosphere. A solution of 3-hydroxy-pyridine (7.27 grams) (76.5 mmoles) and dry pyridine (8.06 grams) (8.25 ml) (101.9 mmoles) in dry CH2Cl2 (200 ml) was added dropwise to the stirred solution at 0° over a period of 1 hour. The mixture was stirred at 0-25° for an additional 2 hours. A stream of nitrogen was passed through the solution to remove most of the phosgene and the solution was then evaporated to dryness to give the title compound which was dried in vacuo for 1 hour and then taken up in dry CH2Cl2 (60 ml) and dry pyridine (60 ml) to give a stock solution of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6](C2CC2)[N:5](N)[CH:4](C2CC2)[N:3]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([N:31]([CH:35]([CH3:37])[CH3:36])C(C)C)C>O1CCOCC1>[CH:35]1([NH:31][C:4]2[N:3]=[C:2]([NH:31][CH:35]3[CH2:36][CH2:37]3)[C:7]([C:8]#[N:9])=[C:6]([N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[N:5]=2)[CH2:37][CH2:36]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CC1=C(C2CC2)N(N)C(C2CC2)N=C1Cl
Solvent: C1COCCO1
Product: N#Cc1c(NC2CC2)nc(NC2CC2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-cyclopropyl-amino-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine and N-ethyl-diisopropylamine in dioxane at 90° C. to yield 2,4-bis-cyclopropylamino-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, light yellow solid; MS: [M+H]+376.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl.O>[F:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH2:9][C@@H:8]([NH:20][C:21](=[O:39])[C@@H:22]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7][C:6]([OH:40])=[O:5])[CH2:11][CH2:12]2
Reactant: COc1cccc(C(=O)N[C@@H](CC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CN2CCc3cc(F)ccc32)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C(=O)N[C@@H](CC(C)(C)C)C(=O)N[C@@H](CC(=O)O)CN2CCc3cc(F)ccc32)c1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
The title compound of example 160 (80 mg, 0.14 mmol) was dissolved in a mixture of TFA, dichloromethane and water in a ratio of 45:45:10 (1 mL) and stirred overnight. The solvent was removed and the reaction was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane 3 times and the combined organics were dried over MgSO4 and the solvent was removed to afford 72 mg (100%) of the title compound as a solid; 1H NMR (MeOD, 400 MHz) δ 0.94 (s, 9H), 1.70 (d, 1H, J=1.1), 2.62 (d, 1H, J=6.5), 2.79-2.93 (m, 2H), 3.06 (dd, 1H, J1=6.0, J2=13.7), 3.19 (dd, 1H, J1=7.7, J2=13.7), 3.45 (dd, 1H, J1=8.6, J2=15.9), 4.42-4.52 (m, 1H), 4.59-4.67 (m, 1H), 6.43 (dd, 1H, J1=4.2, J2=8.5), 6.62-6.68 (m, 1H), 6.72-6.78 (m, 1H), 7.05-7.08 (m, 1H), 7.29-7.38 (m, 3H), 7.96 (d, 1H, J=8.6), 8.37 (d, 1H, J=8.2); HPLC-MS calcd. for C27H34FN3O5 (M+H+) 500.2, found 500.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([O:14]CC)=[O:13])=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:6]=2[CH:27]=1.O1CCOCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([OH:14])=[O:13])=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:6]=2[CH:27]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(Cl)ccc2oc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2c(C(=O)O)c(=O)oc3ccc(Cl)cc23)cc1OC

Procedure:
A mixture of ethyl 6-chloro-4-(3,4-dimethoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylate (1.0 g), dioxane (5 ml), ethanol (5 ml) and 2N-NaOH (12 ml) was refluxed for 1.5 hours, and then, adjusted to pH 2 by adding 2N-HCl. The mixture was stirred for 30 minutes at room temperature, to which water was added to obtain 6-chloro-4-(3,4-dimethoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as crystals. Recrystallization from acetone gave colorless prisms (0.54 g, 58.1%).
Reaction SMILES: [CH3:1][O:2][N:3](C)[C:4](C1N=CN(C2C=C(C3C=CC=CC=3)C=CC=2)C=1)=O.[F:24][C:25]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH:41]=[C:40]([C:42](Cl)=[O:43])[N:39]=[CH:38]3)[CH:32]=2)=[C:29]([O:45][CH3:46])[CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][N:3]([CH3:4])[C:42]([C:40]1[N:39]=[CH:38][N:37]([C:33]2[CH:32]=[C:31]([C:30]3[C:25]([F:24])=[CH:26][CH:27]=[CH:28][C:29]=3[O:45][CH3:46])[CH:36]=[CH:35][CH:34]=2)[CH:41]=1)=[O:43]
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)Cl)c2)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1

Procedure:
This compound is prepared analogously to 12a from 11g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([OH:13])(=[O:12])=[O:11].Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:10]([OH:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cc(F)ccc1O
Reaction time: 0.5 h

Procedure:
200 g (1.78 mol) of 4-fluorophenol are dissolved under a nitrogen atmosphere in 1300 ml of CHCl3 (distilled, dried over CaCl2). Added dropwise to this solution, over a period of 1 hour at room temperature with stirring, are 131 ml (229 g=1.96 mol) of chlorosulfonic acid, a vigorous release of HCl being observed initially, which dies down 30 min after completion and ceases entirely after a further 3 hours. After a reaction time of 24 hours, the precipitated product is filtered off with suction at room temperature under inert gas, washed twice with 200 ml of CHCl3 each time, and dried in vacuo at 1333 Pa and room temperature for 3 hours.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[NH2:18][C:19](N)=[S:20]>S1(CCCC1)(=O)=O>[NH2:18][C:19]1[S:20][C:2]2[C:3]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[CH:6][C:7]=2[N:8]=1
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Solvent: O=S1(=O)CCCC1
Product: Nc1nc2cc([N+](=O)[O-])cc(C(F)(F)F)c2s1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
13.5 g of 2-chloro-3,5-dinitrobenzotrifluoride is slowly introduced, with stirring, into a solution of 15.2 g of thiourea in 50 ml of sulpholane at 100° C. The mixture is stirred at 100° C. for a further 2.5 hours, cooled and the solid is filtered off with suction and the dry residue is thoroughly stirred with 50 ml of carbon disulphide. The solid is filtered off with suction and 7.5 g of material, which is homogeneous by chromatography and has a melting point of 303°-307° C. (decomposition), are obtained. After recrystallisation from pyridine/water (3/1), the melting point rises to 315°-316° C. (decomposition). me+ : 263
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[C@@H:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1.CO.C1(C)C=CC=CC=1>[Pd].O>[CH:24]([N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][C@@H:17]([C:10]1[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:9]=1[OH:8])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Reaction time: 2 h

Procedure:
11 L (R)-[4-Benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol solution formula (H) and Pd/C (10%, 0.18 Kg) and methanol (30 L) was added in SS autoclave cell at 25° C. to 35° C. and the mixture was hydrogenated with 4 kg pressure at 25° C. to 35° C. for 2 hours. The mixture was then filtered and to the filtrate add 4.1 g sodium borohydride portion wise within 15-30 minutes at 25° C. to 35° C. and stir the reaction mass for 30 minutes. Methanol is distilled out under vacuum below 55° C. Further, reaction mass is cooled to 25° C. to 35° C. Toluene (10.0 L) was added followed by addition of RO water (1.50 L). The reaction mass is heated to 50° C. to 55° C. and maintained for 30 minutes. The layers were separated and to the organic layer add toluene (1.6 L) 25° C. to 35° C. The reaction mass is heated to 65° C. to 70° C. and maintain for 30 minutes. Further cooled to 25° C. to 35° C. and stirred for 2 hours and further cooled to 0° C. to 5° C. and stirred for 30 minutes. The reaction mass is washed with toluene (2×0.25 L) to afford the title compound as (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxy methyl phenol having impurity X content about 0.03%.